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Giuseppe PLAZZI

Professore Ordinario
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Sc. Biomediche

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2023 - Dream-enactment behaviours during the COVID-19 pandemic: an international COVID-19 sleep study [Articolo su rivista]
Liu, Y.; Partinen, E.; Chan, N. Y.; Dauvilliers, Y.; Inoue, Y.; De Gennaro, L.; Plazzi, G.; Bolstad, C. J.; Nadorff, M. R.; Merikanto, I.; Bjorvatn, B.; Han, F.; Zhang, B.; Cunha, A. S.; Mota-Rolim, S.; Leger, D.; Matsui, K.; Espie, C. A.; Chung, F.; Morin, C. M.; Sieminski, M.; Thomas, P.; Holzinger, B.; Partinen, M.; Wing, Y. K.

There has been increasing concern about the long-term impact of coronavirus disease 2019 (COVID-19) as evidenced by anecdotal case reports of acute-onset parkinsonism and the polysomnographic feature of increased rapid eye movement sleep electromyographic activity. This study aimed to determine the prevalence and correlates of dream-enactment behaviours, a hallmark of rapid eye movement sleep behaviour disorder, which is a prodrome of α-synucleinopathy. This online survey was conducted between May and August 2020 in 15 countries/regions targeting adult participants (aged ≥18 years) from the general population with a harmonised structured questionnaire on sleep patterns and disorders, COVID-19 diagnosis and symptoms. We assessed dream-enactment behaviours using the Rapid Eye Movement Sleep Behaviour Disorder Single-Question Screen with an additional question on their frequency. Among 26,539 respondents, 21,870 (82.2%) answered all items that were analysed in this study (mean [SD] age 41.6 [15.8] years; female sex 65.5%). The weighted prevalence of lifetime and weekly dream-enactment behaviours was 19.4% and 3.1% and were found to be 1.8- and 2.9-times higher in COVID-19-positive cases, respectively. Both lifetime and weekly dream-enactment behaviours were associated with young age, male sex, smoking, alcohol consumption, higher physical activity level, nightmares, COVID-19 diagnosis, olfactory impairment, obstructive sleep apnea symptoms, mood, and post-traumatic stress disorder features. Among COVID-19-positive cases, weekly dream-enactment behaviours were positively associated with the severity of COVID-19. Dream-enactment behaviours are common among the general population during the COVID-19 pandemic and further increase among patients with COVID-19. Further studies are needed to investigate the potential neurodegenerative effect of COVID-19.

2023 - Narcolepsy and emotions: Is there a place for a theory of mind approach? [Articolo su rivista]
Del Sette, P.; Veneruso, M.; Cordani, R.; Lecce, S.; Varallo, G.; Franceschini, C.; Venturino, C.; Pizza, F.; Plazzi, G.; Nobili, L.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, rapid eye movement sleep-related manifestations, and cataplexy. In the current literature there is general agreement regarding neural correlates of Narcolepsy type 1 that appear to be related to anatomical and functional abnormalities in the hypothalamic region. In the last two decades, researchers shed light on the neurological bases of cataplexy by focusing on the neurobiological correlates of emotions. Although the results of these studies differ, they all point to an impairment in the amygdala and hypothalamus functions that are known to be involved in emotional processing, suggesting an impairment in this domain in narcoleptic patients. Indeed, despite heterogeneous results, several studies showed that narcoleptic patients differed from healthy controls in processing emotional stimuli. From a behavioral point of view, these findings suggest that alterations in emotional processing may be driven, at least in part, by compensatory strategies to avoid or reduce the frequency of cataplexy attacks. Surprisingly, the only study exploring in NT1 the behavioural performances in emotional facial recognition found no differences between NT1 adults and controls. We hypothesize that narcoleptic patients may present an alteration in a more complex socio-cognitive ability that is related to emotional processing, namely Theory of Mind. This review aims to investigate the literature supporting this hypothesis and to propose possible future developments on this topic.

2023 - Resilience and its correlates in patients with narcolepsy type 1 [Articolo su rivista]
D'Alterio, A.; Menchetti, M.; Zenesini, C.; Rossetti, A.; Vignatelli, L.; Franceschini, C.; Varallo, G.; Pizza, F.; Plazzi, G.; Ingravallo, F.

STUDY OBJECTIVES: This study aimed to explore resilience and its possible association with sociodemographic and clinical features in patients with narcolepsy type 1 (NT1). METHODS: This was a cross-sectional study involving patients with NT1 and age-/sex-matched controls (comparison group). Sociodemographic and clinical data were collected through semistructured interviews and validated questionnaires, including the Epworth Sleepiness Scale (ESS), State-Trait Anxiety Inventory (STAI)-State Anxiety, Beck Depression Inventory (BDI), 36-item Short Form Survey (SF-36), and the Resilience Scale (RS). Different statistical approaches were used to investigate the relationship between resilience and NT1 and associations with sociodemographic and clinical features. RESULTS: The participants comprised 137 patients (mean age, 38.0 years; 52.6% female) and 149 controls (39.6 years; 55.7% female). Compared with controls, patients had a significantly lower (122.6 vs 135.5) mean RS score and a 2-fold risk of having low/mild-range resilience (adjusted odds ratio = 1.99, 95% confidence interval 1.13-3.52). Patients with high resilience had sociodemographic and narcolepsy characteristics similar to patients with low resilience, but they reported anxiety and depressive symptomatology less frequently (4.2% vs 55.8% and 58.3%, respectively), and their SF-36 scores were comparable to those of the comparison group. In patients, RS score was strongly associated with STAI-State Anxiety and BDI (rho = -0.57 and -0.56, respectively) and weakly with ESS (rho = -20) scores. CONCLUSIONS: The results of this study suggest that resilience may play a key role in patients' adaptation to NT1. Furthermore, this study supports interventions aimed at increasing patients' resilience and provides a base for further studies, preferably longitudinal and including objective measures, directed toward understanding the relationship between resilience, depression, and quality of life in patients with narcolepsy. CITATION: D'Alterio A, Menchetti M, Zenesini C, et al. Resilience and its correlates in patients with narcolepsy type 1. J Clin Sleep Med. 2023;19(4):719-726.

2023 - The long wave of COVID-19: a case report using Imagery Rehearsal Therapy for COVID-19-related nightmares after admission to intensive care unit [Articolo su rivista]
Rapelli, Giada; Varallo, Giorgia; Scarpelli, Serena; Pietrabissa, Giada; Musetti, Alessandro; Plazzi, Giuseppe; Franceschini, Christian; Castelnuovo, Gianluca

IntroductionThe COVID-19 pandemic caused several psychological consequences for the general population. In particular, long-term and persistent psychopathological detriments were observed in those who were infected by acute forms of the virus and need specialistic care in the Intensive Care Unit (ICU). Imagery rehearsal therapy (IRT) has shown promising results in managing nightmares of patients with different traumas, but it has never been used with patients admitted to ICUs for severe COVID-19 despite this experience being considered traumatic in the literature. MethodsThe purpose of this case study is to describe the application of a four-session IRT for the treatment of COVID-related nightmares in a female patient after admission to the ICU. A 42-year-old Caucasian woman who recovered from a pulmonary rehabilitation program reported shortness of breath, dyspnea, and everyday life difficulties triggered by the long-COVID syndrome. She showed COVID-related nightmares and signs of post-traumatic symptoms (i.e., hyperarousal, nightmares, and avoidance of triggers associated with the traumatic situation). Psychological changes in the aftermath of a trauma, presence, and intensity of daytime sleepiness, dream activity, sleep disturbances, aspects of sleep and dreams, and symptoms of common mental health status are assessed as outcomes at the baseline (during the admission to pneumology rehabilitation) at 1-month (T1) and 3-month follow-up (T2). Follow-up data were collected through an online survey. ResultsBy using IRT principles and techniques, the patient reported a decrease in the intensity and frequency of bad nightmares, an increase in the quality of sleep, and post-traumatic growth, developing a positive post-discharge. ConclusionImagery rehearsal therapy may be effective for COVID-19-related nightmares and in increasing the quality of sleep among patients admitted to the ICU for the treatment of COVID-19. Furthermore, IRT could be useful for its brevity in hospital settings.

2022 - Being creative during lockdown: The relationship between creative potential and COVID-19-related psychological distress in narcolepsy type 1 [Articolo su rivista]
D'Anselmo, A.; Agnoli, S.; Filardi, M.; Pizza, F.; Mastria, S.; Corazza, G. E.; Plazzi, G.

The national lockdown imposed in several countries to counteract the coronavirus disease 2019 (COVID-19) pandemic led to an unprecedented situation with serious effects on mental health of the general population and of subjects affected by heterogeneous diseases. Considering the positive association between narcoleptic symptoms and creativity, we aimed at exploring the psychological distress associated with COVID-19 restrictions and its relationship with depressive symptoms and creativity in patients with narcolepsy type 1 (NT1). A total of 52 patients with NT1 and 50 healthy controls, who completed a previous study on creativity, were contacted during the first lockdown period to complete an online survey evaluating psychological distress related to the COVID-19 outbreak, sleep quality, narcolepsy and depressive symptoms, and creative abilities. The patients with NT1 showed an improvement in subjective sleepiness while controls reported worsening of sleep quality during the lockdown. Depression and NT1 symptom severity proved significant predictors of COVID-19-related distress. Creative performance, namely generative fluency, turned out to be a favourable moderator in the relationship between depression and patients’ distress, reducing the detrimental effect of depression on the patients’ wellbeing. On the contrary, creative originality proved to be a disadvantageous moderator in the relationship between NT1 symptom severity and the distress associated with this traumatic event indicating a higher vulnerability to developing COVID-19-related distress, particularly evident in patients displaying higher originality. Overall, these results highlight a crucial role of creativity in patients with NT1, suggesting that creative potential could be used as a protective factor against the development of distress associated with the lockdown.

2022 - Catastrophizing, Kinesiophobia, and Acceptance as Mediators of the Relationship Between Perceived Pain Severity, Self-Reported and Performance-Based Physical Function in Women with Fibromyalgia and Obesity [Articolo su rivista]
Varallo, G.; Suso-Ribera, C.; Ghiggia, A.; Veneruso, M.; Cattivelli, R.; Usubini, A. G.; Franceschini, C.; Musetti, A.; Plazzi, G.; Fontana, J. M.; Capodaglio, P.; Castelnuovo, G.

Individuals with fibromyalgia and obesity experience significant impairment in physical functioning. Pain catastrophizing, kinesiophobia, and pain acceptance have all been identified as important factors associated with the level of disability. The objective of this study was to evaluate the role of pain catastrophizing, kinesiophobia, and pain acceptance as mediators of the association between perceived pain severity and physical functioning in individuals with fibromyalgia and obesity.

2022 - Child Neurology: A Case Series of Heterogeneous Neuropsychiatric Symptoms and Outcome in Very Early-Onset Narcolepsy Type 1 [Articolo su rivista]
Veneruso, M.; Pizza, F.; Finotti, E.; Amore, G.; Vandi, S.; Filardi, M.; Antelmi, E.; Nobili, L.; Cassio, A.; Pession, A.; Plazzi, G.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy (i.e., sudden loss of muscle tone during wakefulness triggered by emotions), and REM sleep-related manifestations that can present with a peculiar phenotype when arising at a pediatric age. Several features of childhood-onset narcolepsy type 1 are also common in neuropsychiatric conditions; discrete neuropsychiatric comorbidity has also been demonstrated. Here, we report on 3 children with very early narcolepsy type 1. All 3 patients had psychiatric features at the time of symptom onset coupled with peculiar motor disturbances. The course of narcolepsy symptoms also paralleled neuropsychiatric symptoms, suggesting a possible intrinsic link between sleep and psychological features. Multidisciplinary management is mandatory for pediatric narcolepsy type 1 since prompt disease management addressing neuropsychiatric symptoms could lead to better clinical outcomes and quality of life.

2022 - Chromatic Pupillometry in Isolated Rapid Eye Movement Sleep Behavior Disorder [Articolo su rivista]
La Morgia, C.; Romagnoli, M.; Pizza, F.; Biscarini, F.; Filardi, M.; Donadio, V.; Carbonelli, M.; Amore, G.; Park, J. C.; Tinazzi, M.; Carelli, V.; Liguori, R.; Plazzi, G.; Antelmi, E.

Background: Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. Objectives: To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. Methods: iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. Results: We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. Conclusion: The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

2022 - Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort [Articolo su rivista]
Mutti, C.; Brunetti, V.; Figorilli, M.; Liguori, C.; Pizza, F.; Proserpio, P.; Sacco, T.; Pedrazzi, G.; Lecomte, I.; Blanchard, N.; Agostoni, E. C.; Bonanni, E.; Centonze, D.; Cicolin, A.; Della Marca, G.; Ferini-Strambi, L.; Ferri, R.; Gigli, G. L.; Izzi, F.; Liguori, R.; Lodi, R.; Nobili, L.; Parrino, L.; Placidi, F.; Puligheddu, M.; Romigi, A.; Savarese, M. A.; Terzaghi, M.; Plazzi, G.

Introduction: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients’ subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). Methods: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. Results: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. Conclusion: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

2022 - Data-Driven Phenotyping of Central Disorders of Hypersomnolence With Unsupervised Clustering [Articolo su rivista]
Gool, J. K.; Zhang, Z.; Oei, M. S. S. L.; Mathias, S.; Dauvilliers, Y.; Mayer, G.; Plazzi, G.; Del Rio-Villegas, R.; Cano, J. S.; Sonka, K.; Partinen, M.; Overeem, S.; Peraita-Adrados, R.; Heinzer, R.; Martins Da Silva, A.; Hogl, B.; Wierzbicka, A.; Heidbreder, A.; Feketeova, E.; Manconi, M.; Buskova, J.; Canellas, F.; Bassetti, C. L.; Barateau, L.; Pizza, F.; Schmidt, M. H.; Fronczek, R.; Khatami, R.; Lammers, G. J.

Background and ObjectivesRecent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers.MethodsWe used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups.ResultsWe included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters.DiscussionUsing a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features.

2022 - Diagnostic and Therapeutic Approach to Children and Adolescents with Obstructive Sleep Apnea Syndrome (OSA): Recommendations in Emilia-Romagna Region, Italy [Articolo su rivista]
Esposito, S.; Ricci, G.; Gobbi, R.; Vicini, C.; Caramelli, F.; Pizzi, S.; Fadda, A.; Ferro, S.; Plazzi, G.

Obstructive sleep apnoea syndrome (OSA) in paediatrics is a rather frequent pathology caused by pathophysiological alterations leading to partial and prolonged obstruction (hypoventilation) and/or intermittent partial (hypopnoea) or complete (apnoea) obstruction of the upper airways. Paediatric OSA is characterised by daytime and night-time symptoms. Unfortunately, there are few data on shared diagnostic-therapeutic pathways that address OSA with a multidisciplinary approach in paediatric age. This document summarizes recommendations from the Emilia-Romagna Region, Italy, developed in order to provide the most appropriate tools for a multidisciplinary approach in the diagnosis, treatment and care of paediatric patients with OSA. The multidisciplinary group of experts distinguished two different ‘step’ pathways, depending on the age group considered (i.e., under or over two years). In most cases, these pathways can be carried out by the primary care paediatrician, who represents the first filter for approaching the problem. For this reason, it is essential that the primary care paediatrician receives adequate training on how to formulate the diagnostic suspicion of OSA and on what criteria to use to select patients to be sent to the hospital centre. The relationship between the paediatrician of the patient and her/his parents must see a synergy of behaviour between the various players in order to avoid uncertainty about the diagnostic and therapeutic decisions as well as the follow-up phase. The definition and evaluation of the organizational process and outcome indicators of the developed flow-chart, and the impact of its implementation will remain fundamental.

2022 - Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies [Articolo su rivista]
Poggiolini, I.; Gupta, V.; Lawton, M.; Lee, S.; El-Turabi, A.; Querejeta-Coma, A.; Trenkwalder, C.; Sixel-Doring, F.; Foubert-Samier, A.; Pavy-Le Traon, A.; Plazzi, G.; Biscarini, F.; Montplaisir, J.; Gagnon, J. -F.; Postuma, R. B.; Antelmi, E.; Meissner, W. G.; Mollenhauer, B.; Ben-Shlomo, Y.; Hu, M. T.; Parkkinen, L.

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

2022 - Disrupted nighttime sleep and sleep instability in narcolepsy [Articolo su rivista]
Maski, K.; Mignot, E.; Plazzi, G.; Dauvilliers, Y.

STUDY OBJECTIVES: This review aimed to summarize current knowledge about disrupted nighttime sleep (DNS) and sleep instability in narcolepsy, including self-reported and objective assessments, potential causes of sleep instability, health consequences and functional burden, and management. METHODS: One hundred two peer-reviewed publications from a PubMed search were included. RESULTS: DNS is a key symptom of narcolepsy but has received less attention than excessive daytime sleepiness and cataplexy. There has been a lack of clarity regarding the definition of DNS, as many sleep-related symptoms and conditions disrupt sleep quality in narcolepsy (eg, hallucinations, sleep paralysis, rapid eye movement sleep behavior disorder, nightmares, restless legs syndrome/periodic leg movements, nocturnal eating, sleep apnea, depression, anxiety). In addition, the intrinsic sleep instability of narcolepsy results in frequent spontaneous wakings and sleep stage transitions, contributing to DNS. Sleep instability likely emerges in the setting of orexin insufficiency/deficiency, but its exact pathophysiology remains unknown. DNS impairs quality of life among people with narcolepsy, and more research is needed to determine its contributions to cardiovascular risk. Multimodal treatment is appropriate for DNS management, including behavioral therapies, counseling on sleep hygiene, and/or medication. There is strong evidence showing improvement in self-reported sleep quality and objective sleep stability measures with sodium oxybate, but rigorous clinical trials with other pharmacotherapies are needed. Treatment may be complicated by comorbidities, concomitant medications, and mood disorders. CONCLUSIONS: DNS is a common symptom of narcolepsy deserving consideration in clinical care and future research. CITATION: Maski K, Mignot E, Plazzi G, Dauvilliers Y. Disrupted nighttime sleep and sleep instability in narcolepsy. J Clin Sleep Med. 2022;18(1):289-304.

2022 - Disturbances in sleep, circadian rhythms and daytime functioning in relation to coronavirus infection and Long-COVID – A multinational ICOSS study [Articolo su rivista]
Merikanto, I.; Dauvilliers, Y.; Chung, F.; Holzinger, B.; De Gennaro, L.; Wing, Y. K.; Korman, M.; Partinen, M.; Benedict, C.; Bjelajac, A.; Bjorvatn, B.; Yin Chan, N.; Hrubos-Strom, H.; Inoue, Y.; Kirov, R.; Landtblom, A. -M.; Leger, D.; Matsui, K.; Morin, C. M.; Mota-Rolim, S.; Nadorff, M. R.; Penzel, T.; Plazzi, G.; Reis, C.; Yordanova, J.; Kortesoja, L.; Merikanto, ; De Santis, A.; Bolstad, C.; Nadorff, ; de Macedo, T. F.; Cunha, A. S.; Mota-Rolim, ; Nierwetberg, F.; Agami, D.; Schwartsberg, E.; Korman, ; Koumanova, S.; Lyamova, L.; Yordanova, ; Kristoffersson, A.; Berntsson, S.; Liu, Y.; Ferreira, D.; Avdagic, S. C.; Delale, E. A.; Macan, J.; Ross, B.; Vidovic, D.; Lyamova, V. K.

This protocol paper describes the second survey produced by the International Covid Sleep Study (ICOSS) group with the aim to examine the associations between SARS-CoV-2 infection and sleep, sleepiness, and circadian problems as potential predisposing factors for more severe COVID-19 disease profile and for development of Long-COVID in the general population. The survey consists of 47 questions on sleep, daytime sleepiness, circadian rhythm, health, mental wellbeing, life habits, and socioeconomic situation before and during the pandemic, and conditional questions to those reporting having had coronavirus infection, being vaccinated, or suffering from particular sleep symptoms or sleep disorders. Surveys will be administered online between May and November 2021 in Austria, Brazil, Bulgaria, Canada, China, Croatia, Finland, France, Germany, Israel, Italy, Japan, Norway, Portugal, Sweden and USA. Data collected by the survey will give valuable information on the open questions regarding COVID-19 disease risk factors, symptomatology and evolution of Long-COVID, and on other long-term consequences related to the pandemic.

2022 - Evening-types show highest increase of sleep and mental health problems during the COVID-19 pandemic - Multinational study on 19 267 adults [Articolo su rivista]
Merikanto, I.; Kortesoja, L.; Benedict, C.; Chung, F.; Cedernaes, J.; Espie, C. A.; Morin, C. M.; Dauvilliers, Y.; Partinen, M.; De Gennaro, L.; Wing, Y. K.; Chan, N. Y.; Inoue, Y.; Matsui, K.; Holzinger, B.; Plazzi, G.; Mota-Rolim, S. A.; Leger, D.; Penzel, T.; Bjorvatn, B.

Study Objectives: Individual circadian type is a ubiquitous trait defining sleep, with eveningness often associated with poorer sleep and mental health than morningness. However, it is unknown whether COVID-19 pandemic has differentially affected sleep and mental health depending on the circadian type. Here, the differences in sleep and mental health between circadian types are examined globally before and during the COVID-19 pandemic. Methods: The sample collected between May and August 2020 across 12 countries/regions consisted of 19 267 adults with information on their circadian type. Statistical analyses were performed by using Complex Sample procedures, stratified by country and weighted by the number of inhabitants in the country/area of interest and by the relative number of responders in that country/area. Results: Evening-types had poorer mental health, well-being, and quality of life or health than other circadian types during the pandemic. Sleep-wake schedules were delayed especially on working days, and evening-types reported an increase in sleep duration. Sleep problems increased in all circadian types, but especially among evening-types, moderated by financial suffering and confinement. Intermediate-types were less vulnerable to sleep changes, although morningness protected from most sleep problems. These findings were confirmed after adjusting for age, sex, duration of the confinement, or socio-economic status during the pandemic. Conclusions: These findings indicate an alarming increase in sleep and mental health problems, especially among evening-types as compared to other circadian types during the pandemic.

2022 - Exploring Addictive Online Behaviors in Patients with Narcolepsy Type 1 [Articolo su rivista]
Varallo, Giorgia; Musetti, Alessandro; D'Anselmo, Anita; Gori, Alessio; Maria Giusti, Emanuele; Pizza, Fabio; Castelnuovo, Gianluca; Plazzi, Giuseppe; Franceschini, Christian

Background: Narcolepsy type 1 (NT1) is a rare neurological sleep disorder caused by the loss of neurons that produce hypocretin-a peptide that plays a crucial role in addictive behaviors. We aimed to compare, for the first time, levels of problematic online gaming, problematic social media use, and compulsive Internet use between NT1 patients and healthy controls (HC), and to evaluate the association between anxiety, depression, and emotion dysregulation with addictive online behaviors in NT1 patients. Methods: A total of 43 patients with NT1 and 86 sex- and age-matched HC participated in an online cross-sectional survey. Results: NT1 patients did not differ from HC in terms of problematic social media use and compulsive Internet use but displayed higher levels of problematic online gaming compared to HC. Higher levels of emotion dysregulation were significantly associated with higher levels of problematic social media use and compulsive Internet use, while none of the tested factors were associated with problematic online gaming. Conclusion: NT1 patients and HC had similar levels of problematic social media use and compulsive Internet use, but NT1 patients showed higher levels of problematic online gaming. Emotion dysregulation might be an intervention target for reducing compulsive Internet use and problematic social media use.

2022 - Has the COVID-19 Pandemic Traumatized Us Collectively? The Impact of the COVID-19 Pandemic on Mental Health and Sleep Factors via Traumatization: A Multinational Survey [Articolo su rivista]
Holzinger, Brigitte; Nierwetberg, Franziska; Chung, Frances; J Bolstad, Courtney; Bjorvatn, Bjørn; Yin Chan, Ngan; Dauvilliers, Yves; A Espie, Colin; Han, Fang; Inoue, Yuichi; Leger, Damien; Macêdo, Tainá; Matsui, Kentaro; Merikanto, Ilona; M Morin, Charles; A Mota-Rolim, Sérgio; Partinen, Markku; Plazzi, Giuseppe; Penzel, Thomas; Sieminski, Mariusz; Kwok Wing, Yun; Scarpelli, Serena; R Nadorff, Michael; De Gennaro, Luigi

Purpose: The COVID-19 pandemic affects mental health and sleep, resulting in frequent nightmares. Therefore, identifying factors associated with nightmare frequency is important, as it can indicate mental health issues. The study aimed to investigate increases in nightmare frequency comparing the pre-pandemic and pandemic period, and identify its risk factors. Further, the mediating role of post-traumatic stress disorder symptoms between the pandemic and nightmares is explored. Patients and Methods: For this cross-sectional survey data were obtained via self-rating online survey (ICOSS: details in Partinen et al, 2021), which was open to anyone older than 18 years. The final volunteer sample consisted of 15,292 participants, divided according to their nightmare frequency (high: ≥1–2 nights/week; low: <1–2 nights/week). A total of 9100 participants were excluded if answers on variables of interest were missing or receiving rewards for participation. Chi-square tests identified changes of nightmare frequency. Predictors of high nightmare frequency were assessed using logistic regression and presented as Odds Ratios. Post-hoc mediation models were used to investigate the role of post-traumatic stress symptoms (PTSS). Results: The mean age was 41.63 (SD=16.55) with 64.05% females. High nightmare frequency increased significantly from 13.24% to 22.35% during the pandemic. Factors associated with it included self-reported PTSS (OR=2.11), other mental disorders and various sleep disorders or problems. Financial burden due to the pandemic, confinement, having had COVID-19, and work situation during the pandemic were associated with nightmare frequency, those relations were partly mediated through PTSS. Conclusion: Our results display the pandemic influence on nightmare frequency, which in turn connects to multiple mental health and sleep factors. These relations were partly mediated through PTSS. The COVID-19 pandemic appears to have caused traumatization of a substantial proportion of society. Health care workers should consider nightmares in their screening routines, as it might indicate PTSS and/or other mental and sleep disorders.

2022 - Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis [Articolo su rivista]
Zhang, Z.; Dauvilliers, Y.; Plazzi, G.; Mayer, G.; Lammers, G. J.; Santamaria, J.; Partinen, M.; Overeem, S.; Villegas, R. R.; Sonka, K.; Peraita-Adrados, R.; Heinzer, R.; Wierzbicka, A.; Hogl, B.; Manconi, M.; Feketeova, E.; Silva, A. M. D.; Buskova, J.; Bassetti, C. L. A.; Barateau, L.; Pizza, F.; Antelmi, E.; Gool, J. K.; Fronczek, R.; Gaig, C.; Khatami, R.

Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990–2018) and the factors associated with the delay in Europe. Patients and Methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7−13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

2022 - Insomnia in primary care: a survey conducted on Italian patients older than 50 years—results from the “Sonno e Salute” study [Articolo su rivista]
Proserpio, P.; Biggio, G.; Ferri, R.; Girardi, P.; Agostoni, E. C.; Manni, R.; Minervino, A.; Palagini, L.; Plazzi, G.; Nobili, L.; Arnaldi, D.

Insomnia affects one-third of the adult population and is associated with multiple medical conditions. We conducted an observational epidemiological survey to assess (1) the prevalence of insomnia in an Italian group of patients aged over 50 years, presenting directly to the general physician (GP); (2) the association of insomnia with sleepiness and comorbidities; and (3) the pharmacological treatment. The study was carried out by GPs. Each GP was asked to enroll the first patient over 50 years old spontaneously presenting for any medical problems for 5 consecutive days. The Italian version of the Sleep Condition Indicator (SCI) was administered; daytime sleepiness was evaluated by a visual analogic scale (VAS). For every patient, GPs collected information regarding comorbidities and pharmacological treatment for insomnia and evaluated the severity of insomnia using the Clinical Global Impression Severity (CGI-S) scale. A total of 748 patients (mean age 65.12 ± 9.45 years) were enrolled by 149 GPs. Prevalence of insomnia was 55.3%. SCI, VAS, and CGI-S scores were highly correlated between each other (p < 0.0001). At general linear model analysis, the comorbidities more associated with the presence of insomnia were anxiety-depressive disorder (p < 0.001), other psychiatric disorders (p = 0.017), cardiovascular disorders (p = 0.006), and dementia (p = 0.027). A statistically significant correlation was found between SCI score and the use of benzodiazepines (p < 0.001), z-drugs (p = 0.012), antidepressants (p < 0.001), and melatonin-prolonged release (p < 0.001). Insomnia affects half of Italian primary care patients over 50 years and is frequently associated with different medical conditions, sleepiness, and use of multiple—often off-label—drugs.

2022 - Is Whole-Body Cryostimulation an Effective Add-On Treatment in Individuals with Fibromyalgia and Obesity? A Randomized Controlled Clinical Trial [Articolo su rivista]
Varallo, G.; Pitera, P.; Fontana, J. M.; Gobbi, M.; Arreghini, M.; Giusti, E. M.; Franceschini, C.; Plazzi, G.; Castelnuovo, G.; Capodaglio, P.

Pain severity, depression, and sleep disturbances are key targets for FM rehabilitation. Recent evidence suggests that whole-body cryostimulation (WBC) might be an effective add-on treatment in the management of FM. The purpose of this study was to evaluate the effects of an add-on WBC intervention to a multidisciplinary rehabilitation program on pain intensity, depressive symptoms, disease impact, sleep quality, and performance-based physical functioning in a sample of FM patients with obesity. We performed a randomized controlled trial with 43 patients with FM and obesity undergoing a multidisciplinary rehabilitation program with and without the addition of ten 2-min WBC sessions at −110 °C over two weeks. According to our results, the implementation of ten sessions of WBC over two weeks produced additional benefits. Indeed, both groups reported positive changes after the rehabilitation; however, the group that underwent WBC intervention had greater improvements in the severity of pain, depressive symptoms, disease impact, and quality of sleep. On the contrary, with respect to performance-based physical functioning, we found no significant between-group differences. Our findings suggest that WBC could be a promising add-on treatment to improve key aspects of FM, such as pain, depressive symptoms, disease impact and poor sleep quality.

2022 - Longitudinal associations between stress and sleep disturbances during COVID-19 [Articolo su rivista]
Ballesio, Andrea; Zagaria, Andrea; Musetti, Alessandro; Lenzo, Vittorio; Palagini, Laura; Quattropani, Maria Catena; Vegni, Elena; Bonazza, Federica; Filosa, Maria; Manari, Tommaso; Freda, Maria Francesca; Saita, Emanuela; Castelnuovo, Gianluca; Plazzi, Giuseppe; Lombardo, Caterina; Franceschini, Christian

: The psychological consequences of COVID-19 pandemic may include the activation of stress systems, that involve the hypothalamic-pituitary-adrenal axis which influences many physiological functions, including sleep. Despite epidemiological studies evidenced greater prevalence of stress symptoms and sleep disturbances during COVID-19, longitudinal evidence investigating the effects of stress on sleep disturbances during the pandemic is lacking. We collected measures of perceived stress and sleep disturbances during the first wave of COVID-19 (March 2020) and at 8-10 months follow up in a sample of 648 adults (M= 33.52, SD= 12.98 years). Results showed that 39.4% of participants reported moderate to extremely severe stress in March 2020. Prevalence of sleep disturbances was 54.8% in March 2020 and 57.4% at follow-up. Structural equation modelling highlighted that perceived stress in March 2020 significantly predicted sleep disturbances at follow up (β=0.203; p<0.001), even after controlling for baseline sleep disturbances. Results remained significant even after controlling for the effects of covariates including age, sex, depression and anxiety symptoms, and referring to psychological services (β=0.179; p<0.05). Findings confirm the high prevalence of stress symptoms during the COVID-19 pandemic and provide first longitudinal evidence for the effects of perceived stress on sleep disturbances during the pandemic. This article is protected by copyright. All rights reserved.

2022 - Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients [Articolo su rivista]
Lecendreux, M.; Plazzi, G.; Dauvilliers, Y.; Rosen, C. L.; Ruoff, C.; Black, J.; Parvataneni, R.; Guinta, D.; Wang, Y. G.; Mignot, E.

STUDY OBJECTIVES: Evaluate long-term efficacy and safety of sodium oxybate (SXB) in children and adolescents (aged 7-16 years) with narcolepsy with cataplexy. METHODS: A double-blind randomized withdrawal study was conducted. Prior to randomization, SXB-naive participants were titrated to an efficacious and tolerable dose of SXB; participants taking SXB entered on their established dose. Following a 2-week stable-dose period and 2-week, double-blind, randomized withdrawal period, participants entered an open-label period (OLP; ≤ 47 weeks). Efficacy measures during the OLP included number of weekly cataplexy attacks, cataplexy-free days, and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Safety outcomes included treatment-emergent adverse events; assessments of depression, anxiety, and suicidality; and polysomnography. RESULTS: Of 106 enrolled participants, 95 entered and 85 completed the OLP. In SXB-naive participants and participants previously taking SXB, efficacy of SXB established prior to the double-blind, randomized withdrawal period was maintained throughout the OLP for number of weekly cataplexy attacks (median [quartile 1, quartile 3] change from the stable-dose period to end of the OLP: 0.0 [-2.5, 4.9] and 0.0 [-3.4, 2.6], respectively) and ESS-CHAD scores (0.0 [-3.0, 2.5] and 1.0 [-3.0, 3.0], respectively). The median (quartile 1, quartile 3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in OLP week 1 and 3.8 (0.5, 5.5) in week 48. Treatment-emergent adverse events (≥ 5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, upper respiratory tract infection, and dizziness. CONCLUSIONS: SXB demonstrated long-term maintenance of efficacy in pediatric narcolepsy with cataplexy, with a safety profile consistent with that observed in adults. CLINICAL TRIAL REGISTRATION: Registry:; Name: A Multicenter Study of the Efficacy and Safety of Xyrem with an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy; URL:; Identifier: NCT02221869. CITATION: Lecendreux M, Plazzi G, Dauvilliers Y, et al. Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients. J Clin Sleep Med. 2022;18(9):2217-2227.

2022 - Narcolepsy [Articolo su rivista]
Barateau, L.; Pizza, F.; Plazzi, G.; Dauvilliers, Y.

This article addresses the clinical presentation, diagnosis, pathophysiology and management of narcolepsy type 1 and 2, with a focus on recent findings. A low level of hypocretin-1/orexin-A in the cerebrospinal fluid is sufficient to diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and the irreversible loss of hypocretin neurons is responsible for the main symptoms of the disease: sleepiness, cataplexy, sleep-related hallucinations and paralysis, and disrupted nocturnal sleep. The process responsible for the destruction of hypocretin neurons is highly suspected to be autoimmune, or dysimmune. Over the last two decades, remarkable progress has been made for the understanding of these mechanisms that were made possible with the development of new techniques. Conversely, narcolepsy type 2 is a less well-defined disorder, with a variable phenotype and evolution, and few reliable biomarkers discovered so far. There is a dearth of knowledge about this disorder, and its aetiology remains unclear and needs to be further explored. Treatment of narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy and disrupted nocturnal sleep. However, new psychostimulants have been recently developed, and the upcoming arrival of non-peptide hypocretin receptor-2 agonists should be a revolution in the management of this rare sleep disease, and maybe also for disorders beyond narcolepsy.

2022 - Narcolepsy with intermediate cerebrospinal level of hypocretin-1 [Articolo su rivista]
Postiglione, E.; Barateau, L.; Pizza, F.; Lopez, R.; Antelmi, E.; Rassu, A. -L.; Vandi, S.; Chenini, S.; Mignot, E.; Dauvilliers, Y.; Plazzi, G.

Study Objectives: To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). Methods: From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1∗06:02, and median CSF hcrt-1 levels (149.34 pg/mL). Results: Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1∗06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1∗06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. Conclusions: Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1∗06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

2022 - Nightmares in People with COVID-19: Did Coronavirus Infect Our Dreams? [Articolo su rivista]
Scarpelli, S.; Nadorff, M. R.; Bjorvatn, B.; Chung, F.; Dauvilliers, Y.; Espie, C. A.; Inoue, Y.; Matsui, K.; Merikanto, I.; Morin, C. M.; Penzel, T.; Sieminski, M.; Fang, H.; Macedo, T.; Mota-Rolim, S. A.; Leger, D.; Plazzi, G.; Chan, N. Y.; Partinen, M.; Bolstad, C. J.; Holzinger, B.; De Gennaro, L.

Introduction: A growing number of studies have demonstrated that the coronavirus disease-19 (COVID-19) pandemic has severely affected sleep and dream activity in healthy people. To date, no investigation has examined dream activity specifically in COVID-19 patients. Methods: As part of the International COVID-19 Sleep Study (ICOSS), we compared 544 COVID-19 participants with 544 matched-controls. A within-subjects comparison between pre-pandemic and pandemic periods computed separately for controls and COVID-19 participants were performed on dream recall and nightmare frequency (DRF; NF). Also, non-parametric comparisons between controls and COVID-19 participants were carried out. Further, we compared psychological measures between the groups collected during pandemic. Ordinal logistic regression to detect the best predictors of NF was performed. Results: We found that people reported greater dream activity during the pandemic. Comparisons between controls and COVID-19 participants revealed a) no difference between groups concerning DRF in the pre-pandemic period and during the pandemic; b) no difference between groups concerning nightmare frequency in the pre-pandemic period; and c) COVID-19 participants reported significantly higher NF than controls during pandemic (p = 0.003). Additionally, we showed that a) anxiety, depression, post-traumatic stress-disorder (PTSD) symptom scores were higher in COVID-19 participants than controls; and b) quality of life and health as well as wellbeing (WHO-5) scores were significantly higher in controls than COVID-19 participants. Finally, ordinal logistic regression indicates that DRF (p < 0.001), PTSD (p < 0.001), anxiety (p = 0.018), insomnia (p = 0.039), COVID-19 severity (p = 0.014), sleep duration (p = 0.003) and age (p = 0.001) predicted NF. Discussion: Our work shows strong associations between increased nightmares in those reporting having had COVID-19. This suggests that the more that people were affected by COVID-19, the greater the impact upon dream activity and quality of life.

2022 - Portrayals of narcolepsy from 1980 to 2020: a descriptive analysis of stigmatizing content in newspaper articles [Articolo su rivista]
Varallo, Giorgia; Pingani, Luca; Musetti, Alessandro; Galeazzi, Gian Maria; Pizza, Fabio; Castelnuovo, Gianluca; Plazzi, Giuseppe; Franceschini, Christian

Study objectives: The media are the primary source of information about health for the public. The media portrayal of narcolepsy might contribute to the stigmatization of people affected by this condition. This study aimed to describe how narcolepsy is portrayed in newspapers. Methods: We collected 257 newspaper articles from the digital archive of "La Stampa" published between 1980 and 2020 that mentioned key search terms. The content was assessed using an ad-hoc coding schema developed to evaluate the presence of sensationalistic title, negative language, stigmatizing content, stereotypical description, disclosure of a person diagnosed with narcolepsy, person with narcolepsy described as dangerous, presence of an accurate diagnosis, identifiable symptoms, indications about diagnostic and treatment services. The Chi-squared analysis was performed to identify changes over time in the type of content. Results: In 10.9% of the articles, there was a sensationalistic title; inappropriate, negative, and outdated language appeared in 10.5% of the articles. Stigmatizing and stereotypical content were reported in 19.5% and 14.8% of the articles, respectively. In 62.3% of the articles, it was disclosed that a person has narcolepsy, and in 5.1% of the articles patients with narcolepsy are described as dangerous. 30.4% of the articles referred to the presence of an accurate diagnosis, while 16.7% described identifiable symptoms. Services for diagnosis and treatment were mentioned in 24.1% of the articles. Changes over time in the content of articles are discussed. Conclusions: Our findings highlight areas for improvement in the media portrayal of narcolepsy and could help guide the development of new targeted antistigma campaigns.

2022 - Predictive risk factors of phenoconversion in idiopathic REM sleep behavior disorder: the Italian study “FARPRESTO” [Articolo su rivista]
Puligheddu, M.; Figorilli, M.; Antelmi, E.; Arnaldi, D.; Casaglia, E.; D'Aloja, E.; Ferini-Strambi, L.; Ferri, R.; Gigli, G. L.; Ingravallo, F.; Maestri, M.; Terzaghi, M.; Plazzi, G.

Most patients with idiopathic REM sleep behavior disorder (iRBD) will develop an overt α-synucleinopathy over time, with a rate of phenoconversion of 73.5% after 12 years from diagnosis. Several markers of phenoconversion were identified; however, most studies investigated biomarkers separately, with retrospective study designs, in small cohorts or without standardized data collection methods. The risk FActoRs PREdictive of phenoconversion in idiopathic REM sleep behavior disorder: the Italian STudy (FARPRESTO) is a multicentric longitudinal retrospective and prospective study with a cohort of incident (prospective recruitment) and prevalent (retrospective recruitment) iRBD patients, whose primary aim is to stratify the risk of phenoconversion, through the systematic collection by means of electronic case report forms of different biomarkers. Secondary aims are to (1) describe the sociodemographic and clinical characteristics of patients with iRBD; (2) collect longitudinal data about the development of α-synucleinopathies; (3) monitor the impact of iRBD on quality of life and sleep quality; (4) assess the correlation between phenoconversion, cognitive performance, and loss of normal muscle atony during REM sleep; (5) identify RBD phenotypes through evaluating clinical, biological, neurophysiological, neuropsychological, and imaging biomarkers; and (6) validate vPSG criteria for RBD diagnosis. The FARPRESTO study will collect a large and harmonized dataset, assessing the role of different biomarkers providing a unique opportunity for a holistic, multidimensional, and personalized approach to iRBD, with several possible application and impact at different levels, from basic to clinical research, and from prevention to management. The FARPRESTO has been registered at (NCT05262543).

2022 - Proteomic biomarkers of Kleine-Levin syndrome [Articolo su rivista]
Hedou, J.; Cederberg, K. L.; Ambati, A.; Lin, L.; Farber, N.; Dauvilliers, Y.; Quadri, M.; Bourgin, P.; Plazzi, G.; Andlauer, O.; Hong, S. -C.; Huang, Y. -S.; Leu-Semenescu, S.; Arnulf, I.; Taheri, S.; Mignot, E.

STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.

2022 - Rare PSAP Variants and Possible Interaction with GBA in REM Sleep Behavior Disorder [Articolo su rivista]
Sosero, Y. L.; Yu, E.; Estiar, M. A.; Krohn, L.; Mufti, K.; Rudakou, U.; Ruskey, J. A.; Asayesh, F.; Laurent, S. B.; Spiegelman, D.; Trempe, J. -F.; Quinnell, T. G.; Oscroft, N.; Arnulf, I.; Montplaisir, J. Y.; Gagnon, J. -F.; Desautels, A.; Dauvilliers, Y.; Gigli, G. L.; Valente, M.; Janes, F.; Bernardini, A.; Sonka, K.; Kemlink, D.; Oertel, W.; Janzen, A.; Plazzi, G.; Antelmi, E.; Biscarini, F.; Figorilli, M.; Puligheddu, M.; Mollenhauer, B.; Trenkwalder, C.; Sixel-Doring, F.; Cochen De Cock, V.; Monaca, C. C.; Heidbreder, A.; Ferini-Strambi, L.; Dijkstra, F.; Viaene, M.; Abril, B.; Boeve, B. F.; Postuma, R. B.; Rouleau, G. A.; Ibrahim, A.; Stefani, A.; Hogl, B.; Hu, M. T. M.; Gan-Or, Z.

Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA. GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP, in three iRBD patients and none in controls (uncorrected p = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA, which requires additional studies.

2022 - REM sleep behavior disorder with predominant nightmares in a patient with ischemic pontine lesions [Articolo su rivista]
Biscarini, F.; Montini, A.; Antelmi, E.; Vandi, S.; Pizza, F.; Plazzi, G.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia typically associated with synucleinopathy and evolving to neurodegenerative disorders. RBD is caused by impairment of brainstem nuclei controlling REM sleep muscle atonia. Rarely, focal lesions of the brainstem can cause secondary RBD. We present the case of a 74-year-old patient, previously evaluated at age 70 years for insomnia and periodic limb movements during sleep, who then rapidly developed unpleasant dreams with minor motor behavior, affecting his sleep quality. Polysomnography recorded REM sleep without atonia and motor behaviors in REM sleep. Ischemic lesions in the pons were detected by magnetic resonance imaging. Clinical, biological, and instrumental biomarkers of neurodegeneration were repeatedly negative at 2 years' follow-up. Although rare, a lesional cause of RBD must be considered in cases of atypical presentation and without evidence of neurodegeneration. The complaint of unpleasant dreams suggests a possible role of brainstem nuclei controlling REM sleep atonia in affecting oneiric content. CITATION: Biscarini F, Montini A, Antelmi E, Vandi S, Pizza F, Plazzi G. REM sleep behavior disorder with predominant nightmares in a patient with ischemic pontine lesions. J Clin Sleep Med. 2022;18(3):945-948.

2022 - Short report. Cooking for autism: a pilot study of an innovative culinary laboratory for Italian adolescents and emerging adults with autism spectrum disorder [Articolo su rivista]
Veneruso, M.; Varallo, G.; Franceschini, C.; Mercante, A.; Rossetti, M.; Rebuttini, A.; Mantovani, A.; Musetti, A.; Castelnuovo, G.; Nobili, L.; Nardocci, F.; Plazzi, G.

Background: Adolescence and emerging adulthood are critical periods for young people with autism spectrum disorder (ASD). However, there is a lack of appropriate and affordable services available. Aims: The Il Tortellante® is an Italian project aimed at promoting adaptive behavior and social skills, and at reducing the severity of symptomatology through a culinary group intervention in which young people with ASD learn to make fresh pasta by hand. Methods: A longitudinal study was conducted. Procedure: Before and after the intervention, 20 participants were assessed based on the severity of symptoms, social skills, and adaptive behaviors. Outcome and results: According to our findings, severity of symptoms and daily living skills improved significantly. Conclusion: A culinary intervention may be useful for adolescents and young adults with ASD to improve daily living skills and reduce ASD-related symptomatology. Implication: Services and associations may consider developing a culinary laboratory for people with ASD to improve group intervention proposals for adolescents and emerging adults. What this paper adds?: This paper offers one of the first investigations of the impact of a culinary laboratory on ASD symptoms, social skills, and adaptive behavior in adolescents and young adults diagnosed with ASD. This group intervention could contribute to expand the range of interventions targeted at adolescents and young adults with ASD, to reduce the severity of symptoms, and to promote adaptive behaviors.

2022 - Sleep disturbances and sleep disorders as risk factors for chronic postsurgical pain: A systematic review and meta-analysis [Articolo su rivista]
Varallo, G.; Giusti, E. M.; Manna, C.; Castelnuovo, G.; Pizza, F.; Franceschini, C.; Plazzi, G.

This systematic review and meta-analysis aimed at evaluating the role of sleep disturbances and sleep disorders in influencing presence and intensity of chronic postsurgical pain (CPSP). We included cohort studies which enrolled adults, assessed sleep disturbances or disorders before surgery, measured pain intensity, presence of pain, or opioid use at least three months after surgery. Eighteen studies were included in a narrative synthesis and 12 in a meta-analysis. Sleep disturbances and disorders were significantly related to CPSP, with a small effect size, r = 0.13 (95% CI 0.06–0.20). The certainty of evidence was rated low due to risk of bias and heterogeneity. In subgroup analyses the above association was significant in studies that used pain intensity as the outcome, but not in those that used presence of pain; in studies on patients who underwent total knee arthroplasty or other surgeries, but not in those on patients who had breast cancer surgery or total hip arthroplasty; in the single study that assessed insomnia and in studies that assessed sleep disturbances as predictors. A meta-regression showed that the follow-up length was positively associated with the overall estimate. Our findings suggest that presurgical sleep disturbances and disorders should be evaluated to detect patients at risk for CPSP. Registration:

2022 - Subjective sleep alterations in healthy subjects worldwide during COVID-19 pandemic: A systematic review, meta-analysis and meta-regression [Articolo su rivista]
Scarpelli, S.; Zagaria, A.; Ratti, P. -L.; Albano, A.; Fazio, V.; Musetti, A.; Varallo, G.; Castelnuovo, G.; Plazzi, G.; Franceschini, C.

Objective: We conducted a systematic review and meta-analysis to provide an update on sleep quality in different world areas and better characterize subjective sleep alterations during the COVID-19 pandemic. Considering gender distribution and specific pandemic-related parameters, we also intend to identify significant predictors of sleep problems. Methods: Six electronic databases were searched from December 2019 to November 2021 for studies investigating sleep during COVID-19 employing the Pittsburgh Sleep Quality Index, the Medical Outcomes Study Sleep, the Insomnia Severity Index or the Epworth Sleepiness Scale. Random-effects models were implemented to estimate the pooled raw means of subjective sleep alterations. Also, we considered the role of several pandemic-related parameters (i.e., days from the first COVID-19 case, government stringency index, new cases for a million people, new deaths for a million people) by means of meta-regression analyses. Results: A total of 139 studies were selected. The pooled mean of the global Pittsburgh Sleep Quality Index score (PSQIgen) was 6.73 (95% CI, 6.61–6.85). The insomnia severity index score was reported from 50 studies with a pooled mean of 8.44 (95% CI, 7.53–9.26). Subgroup analyses confirmed that most subcategories had poor sleep quality and subclinical insomnia. Meta-regressions showed that PSQIgen was predicted by days from the first COVID-19 case and government restrictions with a negative slope and by female gender with a positive slope. The government stringency index was positively correlated with the direct subjective evaluation of sleep quality. Conclusions: We found an overall impaired sleep and widespread subthreshold insomnia during the COVID-19 pandemic. The female percentage seems to be the best predictor of impaired sleep quality, consistently to the available literature. Noteworthy, sleep alterations were inversely associated with governmental restrictions and decreased during the pandemic. Our results give a contribution to critically orienting further studies on sleep since COVID-19 pandemic.

2022 - The European Sleep Research Society – past, present and future [Articolo su rivista]
Deboer, Tom; Sif Arnardóttir, Erna; Landolt, Hans-Peter; Hervé Luppi, Pierre; Mcnicholas, Walter T.; Pevernagie, Dirk; Plazzi, Giuseppe; board of the European Sleep Research Society (ESRS), The

It is 50 years ago, in 1972, that the founding conference of the European Sleep Research Society (ESRS) was organised in Basel. Since then the Society has had 13 presidents and a multitude of board members and has organised, among other things, another 24 congresses. At this 50th anniversary, as the 26th ESRS congress is approaching, we have summarised the history of the ESRS. In this review, we provide a background to show why the foundation of a European society was a logical step, and show how, in the course of the past 50 years, the Society changed and grew. We give special attention to some developments that occurred over the years and discuss where the ESRS stands now, and how we foresee its future.

2022 - The importance of social zeitgeber in paediatric type 1 narcolepsy: What we can learn from the COVID-19 restrictions adopted in Italy? [Articolo su rivista]
Filardi, M.; D'Anselmo, A.; Mazzoni, A.; Moresco, M.; Pizza, F.; Plazzi, G.

The lockdown due to the new coronavirus pandemic (COVID-19) has led to unparalleled changes in several aspects of human behaviour. During the lockdown, the general population delayed sleep timing and spent more time in bed; however, little is known on the effects of COVID-19 restriction on children and adolescents suffering type 1 narcolepsy. In the last months of 2019, we performed follow-up actigraphy in 18 type 1 narcolepsy children and adolescents under stable pharmacological treatment with sodium oxybate. We contacted these patients for a follow-up actigraphy during the first Italian lockdown. Actigraphs and the Epworth Sleepiness Scale for children and adolescents (ESS-CHAD) have been sent to participants’ homes. Differences in motor activity were analysed through functional linear modelling. During lockdown, type 1 narcolepsy children and adolescents went to bed and woke up later, slept more during the daytime and napped more frequently. No difference emerged in time in bed, estimated total sleep time and nocturnal sleep quality. Similarly, no difference emerged in ESS-CHAD and body mass index. The time-series analysis of motor activity documented reduced activity during the early morning and in the evening during the lockdown period compared with pre-lockdown. Our study objectively showed that type 1 narcolepsy children and adolescents delayed the sleep phase and slept more during the daytime during the lockdown. The analysis of type 1 narcolepsy children and adolescents’ behaviour during the lockdown has provided new information that could pave the way to a personalized school programme.

2022 - The Interplay Between Problematic Online Pornography Use, Psychological Stress, Emotion Dysregulation and Insomnia Symptoms During the COVID-19 Pandemic: A Mediation Analysis [Articolo su rivista]
Musetti, A.; Gori, A.; Alessandra, A.; Topino, E.; Terrone, G.; Plazzi, G.; Cacioppo, M.; Franceschini, C.

Purpose: Although a link between problematic online pornographic use (POPU) and insomnia symptoms has been established, psychological and psychopathological mechanisms underlying this relationship are still not clear. Psychological stress and emotion dysregulation have been pointed out as relevant in the development and maintenance of insomnia. This study aims to explore the associations between POPU, psychological stress, emotion dysregulation and insomnia symptoms and to understand the mediating role of psychological stress and emotion dysregulation in the relationship between POPU and insomnia symptoms. Participants and Methods: A sample of 776 Italian adults aged 19–48 years (51.4% female; M age = 28.49; SD = 7.33) completed questionnaires regarding demographics, COVID-19-related variables, POPU, psychological stress, emotion dysregulation, and insomnia symptoms. Results: After controlling for demographic covariates and COVID-19-related variables, multiple mediation model showed that higher psychological stress and emotion dysregulation fully mediated the link between POPU and insomnia. Conclusion: The findings underscore the significance of the negative consequences of POPU and underline the importance of working on this and its effects on psychological stress and emotion dysregulation to limit insomnia.

2022 - The Mediating Role of Emotion Dysregulation and Problematic Internet Use in the Relationship Between Negative Affect and Excessive Daytime Sleepiness: A Structural Equation Model [Articolo su rivista]
Usubini, A. G.; Terrone, G.; Varallo, G.; Cattivelli, R.; Plazzi, G.; Castelnuovo, G.; Schimmenti, A.; Musetti, A.; Franceschini, C.

Purpose: The present study aimed to explore the mediating role of emotion dysregulation and problematic Internet use in the relationship between negative affect and excessive daytime sleepiness. Methods: This cross-sectional study included 664 Italian adults aged between 18 and 70 years (M = 32.13; SD = 11.71). Participants were asked to complete the Depression Anxiety Stress Scale, the Difficulties in Emotion Regulation Scale, the Compulsive Internet Use Scale-7, and the Epworth Sleepiness Scale to assess negative affect, emotion dysregulation, problematic internet use, and excessive daytime sleepiness, respectively. Results: According to our results there are significant associations between negative affect, emotion dysregulation, problematic Internet use, and daytime sleepiness. Moreover, the structural equation model showed good fit indices. Emotion dysregulation and problematic Internet use partially mediated the relationship between negative mood and excessive daytime sleepiness. Conclusion: By exploring the role of emotion dysregulation on the association between excessive daytime sleepiness and its possible predictors, our study might represent an important step toward the implementation of psychological intervention for reducing excessive daytime sleepiness. Emotion dysregulation appears to play a significant role in explaining the relationship between negative affect, problematic Internet use, and excessive daytime sleepiness. Thus, it should be considered a treatment target for reducing excessive daytime sleepiness.

2022 - The orexin story, sleep and sleep disturbances [Articolo su rivista]
Pizza, F.; Barateau, L.; Dauvilliers, Y.; Plazzi, G.

The orexins, also known as hypocretins, are two neuropeptides (orexin A and B or hypocretin 1 and 2) produced by a few thousand neurons located in the lateral hypothalamus that were independently discovered by two research groups in 1998. Those two peptides bind two receptors (orexin/hypocretin receptor 1 and receptor 2) that are widely distributed in the brain and involved in the central physiological regulation of sleep and wakefulness, orexin receptor 2 having the major role in the maintenance of arousal. They are also implicated in a multiplicity of other functions, such as reward seeking, energy balance, autonomic regulation and emotional behaviours. The destruction of orexin neurons is responsible for the sleep disorder narcolepsy with cataplexy (type 1) in humans, and a defect of orexin signalling also causes a narcoleptic phenotype in several animal species. Orexin discovery is unprecedented in the history of sleep research, and pharmacological manipulations of orexin may have multiple therapeutic applications. Several orexin receptor antagonists were recently developed as new drugs for insomnia, and orexin agonists may be the next-generation drugs for narcolepsy. Given the broad range of functions of the orexin system, these drugs might also be beneficial for treating various conditions other than sleep disorders in the near future.

2022 - The Relationship Between Resilience and Sleep Quality During the Second Wave of the COVID-19 Pandemic: A Longitudinal Study [Articolo su rivista]
Lenzo, V.; Sardella, A.; Musetti, A.; Freda, M. F.; Lemmo, D.; Vegni, E.; Borghi, L.; Plazzi, G.; Palagini, L.; Castelnuovo, G.; Cattivelli, R.; Mariani, R.; Michelini, G.; Manari, T.; Saita, E.; Quattropani, M. C.; Franceschini, C.

Purpose: Previous studies showed poor sleep quality during the first Italian lockdown consequent to the quick spread of the virus. Poor sleep quality remained stable during the so-called “second wave”, which started in Autumn 2020. This study aimed to compare sleep quality between the two waves of contagions and to examine the effect of resilience, together with sociodemographic and COVID-related variables, on sleep quality during the second wave. Patients and Methods: A total of 648 participated in this longitudinal study through an online survey during the first lockdown consequent to the COVID-19 and during the second wave. The Medical Outcomes Study—Sleep Scale (MOS-SS) and the Resilience Scale (RS) were administered. Sociodemographic and COVID-related information were also collected. Results: The results showed sleep quality slightly increased in the second wave, even though with a small effect size. Correlational analysis showed that resilience is inversely correlated with sleep quality measured in the two waves. Sleep quality during the second wave was positively correlated with sleep quality in the first lockdown. Likewise, the results of multiple regression revealed that the sleep quality in the first lockdown and resilience were significant predictors of sleep quality during the second wave. Conclusion: These findings highlighted that the prevalence of poor sleepers remained high during the second wave. Together with the sleep quality in the first lockdown, resilience represents an important factor related to sleep quality during the second wave. Interventions to improve sleep quality among the general population should take into account these findings.

2022 - The role of mtDNA haplogroups on metabolic features in narcolepsy type 1 [Articolo su rivista]
Caporali, L.; Moresco, M.; Pizza, F.; La Morgia, C.; Fiorini, C.; Strobbe, D.; Zenesini, C.; Hooshiar Kashani, B.; Torroni, A.; Pagotto, U.; Carelli, V.; Plazzi, G.

Narcolepsy type 1 (NT1) is due to selective loss of hypocretin (hcrt)-producing-neurons. Hcrt is a neuropeptide regulating the sleep/wake cycle, as well as feeding behavior. A subset of NT1 patients become overweight/obese, with a dysmetabolic phenotype. We hypothesized that mitochondrial DNA (mtDNA) sequence variation might contribute to the metabolic features in NT1 and we undertook an exploratory survey of mtDNA haplogroups in a cohort of well-characterized patients. We studied 246 NT1 Italian patients, fully defined for their metabolic features, including obesity, hypertension, low HDL, hypertriglyceridemia and hyperglycemia. For haplogroup assignment, the mtDNA control region was sequenced in combination with an assessment of diagnostic markers in the coding region. NT1 patients displayed the same mtDNA haplogroups (H, HV, J, K, T, U) frequency as those reported in the general Italian population. The majority of NT1 patients (64%) were overweight: amongst these, 35% were obese, 48% had low HDL cholesterol levels, and 31% had hypertriglyceridemia. We identified an association between haplogroups J, K and hypertriglyceridemia (P = 0.03, 61.5% and 61.5%, respectively vs. 31.3% of the whole sample) and after correction for age and sex, we observed a reduction of these associations (OR = 3.65, 95%CI = 0.76–17.5, p = 0.106 and 1.73, 0.52–5.69, p = 0.368, respectively). The low HDL level showed a trend for association with haplogroup J (P = 0.09, 83.3% vs. 47.4% of the whole sample) and after correction we observed an OR = 6.73, 95%CI = 0.65–69.9, p = 0.110. Our study provides the first indication that mtDNA haplogroups J and K can modulate metabolic features of NT1 patients, linking mtDNA variation to the dysmetabolic phenotype in NT1.

2022 - Validation of the Pediatric Narcolepsy Screening Questionnaire (PNSQ): A cross-sectional, observational study [Articolo su rivista]
Morris, S.; Plazzi, G.; de la Loge, C.; Marrel, A.; Profant, J.; Steininger, T. L.; Lin, J.; Owens, J. A.

Objective/Background: This study evaluated psychometric properties of the Pediatric Narcolepsy Screening Questionnaire (PNSQ), developed in response to the difficulty of identifying pediatric narcolepsy. Patients/Methods: The initial PNSQ was updated following debriefing interviews with parents of children with suspected/diagnosed narcolepsy. Subsequently, newly recruited caregivers were categorized into groups: clinician-confirmed narcolepsy, other sleep problems (OSP), and no sleep problems (controls). Caregivers completed the 11-item PNSQ assessing narcolepsy symptomatology. PNSQ psychometric properties were evaluated; mean PNSQ Total Score (TS) was compared inter-group using analysis of variance. Results: The analysis population (N = 158) included patients with narcolepsy (n = 49), OSP (n = 55), and controls (n = 54); mean ± SD age was 13.8 ± 2.8, 10.2 ± 4.3, and 10.0 ± 3.8 years, respectively. Inter-item Pearson correlations (range, 0.22–0.75) indicated good construct validity. Principal component analysis confirmed unidimensionality. Item discriminative power was high for narcolepsy vs control (range, 0.693–0.936) and lower for narcolepsy vs OSP (range, 0.584–0.729). The latent trait was well covered (separation index = 0.868). Item 7 (vivid dreams/nightmares), having low discriminative power and specificity, was removed. Cronbach's alpha (final PNSQ) indicated high internal consistency reliability (raw alpha = 0.88). Mean ± SD PNSQ TS (range, 0–50) in the narcolepsy, OSP, and control groups were 34.98 ± 7.98, 25.20 ± 9.43, and 9.54 ± 9.38, respectively (nominal P < 0.0001). Classification by PNSQ TS was defined: PNSQ+ (likely narcolepsy, TS ≥ 29), PNSQ 0 (likely OSP, TS 19–28), and PNSQ− (narcolepsy unlikely, TS ≤ 18); patients with narcolepsy were classified as PNSQ+ (79.6%), PNSQ 0 (18.4%), and PNSQ− (2.0%). Conclusions: The PNSQ demonstrated good psychometric properties and excellent performance discriminating narcolepsy, OSP, and control groups.

2021 - A practical guide to the pharmacological and behavioral therapy of Narcolepsy [Articolo su rivista]
Franceschini, Christian; Pizza, Fabio; Cavalli, Francesca; Plazzi, Giuseppe

Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients' quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.

2021 - Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder [Articolo su rivista]
Miglis, M. G.; Adler, C. H.; Antelmi, E.; Arnaldi, D.; Baldelli, L.; Boeve, B. F.; Cesari, M.; Dall'Antonia, I.; Diederich, N. J.; Doppler, K.; Dusek, P.; Ferri, R.; Gagnon, J. -F.; Gan-Or, Z.; Hermann, W.; Hogl, B.; Hu, M. T.; Iranzo, A.; Janzen, A.; Kuzkina, A.; Lee, J. -Y.; Leenders, K. L.; Lewis, S. J. G.; Liguori, C.; Liu, J.; Lo, C.; Ehgoetz Martens, K. A.; Nepozitek, J.; Plazzi, G.; Provini, F.; Puligheddu, M.; Rolinski, M.; Rusz, J.; Stefani, A.; Summers, R. L. S.; Yoo, D.; Zitser, J.; Oertel, W. H.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

2021 - BMI changes in paediatric type 1 narcolepsy under sodium oxybate treatment [Articolo su rivista]
Ponziani, Virginia; Pizza, Fabio; Zenesini, Corrado; Vignatelli, Luca; Pession, Andrea; Plazzi, Giuseppe

Paediatric Type 1 Narcolepsy (NT1) is often associated with overweight and obesity. Sodium oxybate (SO), approved for the treatment of narcolepsy with cataplexy from the age of 7 years old in US, has been associated with weight loss, although longitudinal paediatric studies are lacking. We report a retrospective cohort of 129 consecutive patients with a 4 years follow-up, to analyse the impact of different pharmacological treatments on BMI z-score. At baseline the prevalence of obesity and overweight was 26.4 % (34/129) and 29.5% (38/129), respectively. Patients were divided in 3 groups: children treated with SO alone (group 1), with SO-combined therapy (group 2), and without SO (group 3). At the end of the first year of follow-up, group 1 and group 2 showed a significant BMI z-score reduction compared to baseline: from 1.2±1.1 to 0.4±1.4 for group 1 (p < 0.001), and from 1.4±1.1 to 1±1.3 for group 2 (p = 0.002), independently from baseline clinical features. In the second year only group 2 experienced a further and significant BMI z-score decrease (from 1.0±1.2 to 0.6 ± 1.2, p = 0.037). No further significant BMI z-score changes were observed in SO treated patients in the following years. Instead, children treated without SO developed a significant weight increase between the second and third year of therapy (BMI z-score from 0.3±0.9 to 0.5±0.9). In conclusion, SO treatment in paediatric NT1 is associated with a favourable weight reduction in the first year of treatment.

2021 - Cardiovascular disorders in narcolepsy: Review of associations and determinants [Articolo su rivista]
Jennum, P. J.; Plazzi, G.; Silvani, A.; Surkin, L. A.; Dauvilliers, Y.

Narcolepsy type 1 (NT1) is a lifelong disorder of sleep-wake dysregulation defined by clinical symptoms, neurophysiological findings, and low hypocretin levels. Besides a role in sleep, hypocretins are also involved in regulation of heart rate and blood pressure. This literature review examines data on the autonomic effects of hypocretin deficiency and evidence about how narcolepsy is associated with multiple cardiovascular risk factors and comorbidities, including cardiovascular disease. An important impact in NT1 is lack of nocturnal blood pressure dipping, which has been associated with mortality in the general population. Hypertension is also prevalent in NT1. Furthermore, disrupted nighttime sleep and excessive daytime sleepiness, which are characteristic of narcolepsy, may increase cardiovascular risk. Patients with narcolepsy also often present with other comorbidities (eg, obesity, diabetes, depression, other sleep disorders) that may contribute to increased cardiovascular risk. Management of multimorbidity in patients with narcolepsy should include regular assessment of cardiovascular health (including ambulatory blood pressure monitoring), mitigation of cardiovascular risk factors (eg, cessation of smoking and other lifestyle changes, sleep hygiene, and pharmacotherapy), and prescription of a regimen of narcolepsy medications that balances symptomatic benefits with cardiovascular safety.

2021 - Case Report: Burden of Illness in Narcolepsy Type 1: Hikikomori in a Teenage Girl [Articolo su rivista]
Filardi, M.; Blunda, V.; Vandi, S.; Musetti, A.; Posar, A.; Visconti, P.; Pizza, F.; Plazzi, G.; Franceschini, C.

Narcolepsy type 1 (NT1) deeply impacts on quality of life, especially during adolescence, with NT1 children and adolescents that frequently report difficulties in integration with peers and decreased participation in after-school activities. Here we describe the case of NT1 teenager girl presenting with severe physical and social withdrawal, fulfilling the proposed diagnostic criteria for hikikomori, together with the classic NT1 symptoms. Social withdrawal is an overlooked phenomenon among NT1 children and adolescents that, if present, require a multidisciplinary approach and personalized interventions, but patients can benefit from NT1 pharmacological treatment.

2021 - Cognitive dysfunction in central disorders of hypersomnolence: A systematic review [Articolo su rivista]
Filardi, M.; D'Anselmo, A.; Agnoli, S.; Rubaltelli, E.; Mastria, S.; Mangiaruga, A.; Franceschini, C.; Pizza, F.; Corazza, G. E.; Plazzi, G.

Central disorders of hypersomnolence (CDH) are characterized by excessive daytime sleepiness not related to comorbid sleep or medical disturbances. We systematically examined scientific literature on cognitive functions in patients suffering from CDH. Forty-eight studies proved eligible and were analyzed separately for Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2), Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Results were grouped into the cognitive domains of attention, memory, executive functions and higher order cognition. Consistent attention impairments emerged in NT1, NT2 and IH patients, with NT1 patients showing the most compromised profile. Memory functions are largely unimpaired in CDH patients except for KLS patients who display memory deficit. Executive functions and higher-order cognition have been assessed in NT1 while they received little-to-no attention in the other CDH. NT1 patients display high performance in executive functions but exhibit a complex pattern of impairment in higher-order cognition, showing poor decision-making and impaired emotional processing. Moreover, NT1 patients show increased creative abilities. Assessing and monitoring cognitive impairments experienced by CDH patients will allow the design of personalized interventions, parallel to pharmacological treatment, aimed at improving daytime functioning and quality of life of these patients.

2021 - Combining Information on Nocturnal Rem Sleep Latency and Atonia to Facilitate Diagnosis of Pediatric Narcolepsy Type 1 [Articolo su rivista]
Silvani, Alessandro; Vandi, Stefano; Pizza, Fabio; Antelmi, Elena; Ferri, Raffaele; Plazzi, Giuseppe

the diagnosis of narcolepsy type 1 (NT1) at its onset in children and adolescents is often difficult, with substantial diagnostic delay. We aimed to test and validate the effectiveness of rapid-eye-movement (REM) sleep latency (REML), the REM sleep atonia index (RAI), and their combination for the automatic identification of pediatric patients with NT1 based on the standard scoring of nocturnal polysomnograms.

2021 - Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder [Articolo su rivista]
Mufti, K.; Rudakou, U.; Yu, E.; Krohn, L.; Ruskey, J. A.; Asayesh, F.; Laurent, S. B.; Spiegelman, D.; Arnulf, I.; Hu, M. T. M.; Montplaisir, J. Y.; Gagnon, J. -F.; Desautels, A.; Dauvilliers, Y.; Gigli, G. L.; Valente, M.; Janes, F.; Hogl, B.; Stefani, A.; Holzknecht, E.; Sonka, K.; Kemlink, D.; Oertel, W.; Janzen, A.; Plazzi, G.; Antelmi, E.; Figorilli, M.; Puligheddu, M.; Mollenhauer, B.; Trenkwalder, C.; Sixel-Doring, F.; Cochen De Cock, V.; Monaca, C. C.; Heidbreder, A.; Ferini-Strambi, L.; Dijkstra, F.; Viaene, M.; Abril, B.; Boeve, B. F.; Postuma, R. B.; Rouleau, G. A.; Gan-Or, Z.

Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.

2021 - Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study [Articolo su rivista]
Doppler, K; Antelmi, E; Kuzkina, A; Donadio, V; Incensi, A; Plazzi, G; Pizza, F; Marelli, S; Ferini-Strambi, L; Tinazzi, M; Mayer, G; Sittig, E; Booij, J; Sedghi, A; Oertel, W H; Volkmann, J; Sommer, C; Janzen, A; Liguori, R

Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017.

2021 - Dream Activity in Narcoleptic Patients During the COVID-19 Lockdown in Italy [Articolo su rivista]
Scarpelli, S.; Alfonsi, V.; D'Anselmo, A.; Gorgoni, M.; Musetti, A.; Plazzi, G.; De Gennaro, L.; Franceschini, C.

Some studies highlighted that patients with narcolepsy type-1 (NT1) experience high lucid dream frequency, and this phenomenon has been associated with a creative personality. Starting from the well-known “pandemic effect” on sleep and dreaming, we presented a picture of dream activity in pharmacologically treated NT1 patients during the Italian lockdown. Forty-three NT1 patients completed a web-survey during Spring 2021 and were compared with 86 matched-controls. Statistical comparisons revealed that: (a) NT1 patients showed greater sleepiness than controls; (b) controls showed higher sleep disturbances than NT1 patients, and this result disappeared when the medication effect in NT1 was controlled; (c) NT1 patients reported higher lucid dream frequency than controls. Focusing on dreaming in NT1 patients, we found that (a) nightmare frequency was correlated with female gender, longer sleep duration, higher intrasleep wakefulness; (b) dream recall, nightmare and lucid dream frequency were positively correlated with sleepiness. Comparisons between low and high NT1 lucid dreamers showed that patients more frequently experiencing lucid dreams reported a greater influence of dreaming during wakefulness, especially concerning problem-solving and creativity. Overall, our results are consistent with previous studies on pandemic dreaming carried out on healthy subjects. Moreover, we confirmed a link between lucidity and creativity in NT1 patients. Considering the small sample size and the cross-sectional design, our findings cannot provide a causal relationship between lucid dreams and the COVID-19 lockdown. Nevertheless, they represent a first contribution to address future studies on this issue, suggesting that some stable characteristics could interact with changes provoked by the pandemic.

2021 - Dreams and nightmares during the first and second wave of the covid-19 infection: A longitudinal study [Articolo su rivista]
Scarpelli, S.; Alfonsi, V.; Gorgoni, M.; Musetti, A.; Filosa, M.; Quattropani, M. C.; Lenzo, V.; Vegni, E.; Borghi, L.; Margherita, G.; Freda, M. F.; Saita, E.; Cattivelli, R.; Castelnuovo, G.; Manari, T.; Plazzi, G.; De Gennaro, L.; Franceschini, C.

Recent literature shows that the Coronovirus-19 (COVID-19) pandemic has provoked significant changes in dreaming. The current study intends to provide an update about dream variable changes during the second wave of COVID-19. A total of 611 participants completed a web survey from December 2020 to January 2021. Statistical comparisons showed that subjects had lower dream-recall frequency, nightmare frequency, lucid-dream frequency, emotional intensity, and nightmare distress during the second than the first wave of the pandemic. Dreams had a higher negative tone during the second than first wave. We revealed significant differences concerning post-traumatic growth, sleep-related post-traumatic stress disorder (PTSD) symptoms and sleep measures between groups obtained as a function of the changes in the oneiric frequency between the first and second waves. We also found significant correlations between qualitative/emotional dream features and COVID-19-related factors (job change, forced quarantine, having COVID-19 infected relatives/friends, or asking for mental health help). Overall, we found that the second wave affected fewer quantitative features of dream activity and there was less emotional intensity. Moreover, we confirmed the relationship between nightmares and the high risk of PTSD when subjects were grouped as a function of the increasing/decreasing frequency. Finally, our findings are partly coherent with the continuity hypothesis between oneiric and waking experiences.

2021 - European guideline and expert statements on the management of narcolepsy in adults and children [Articolo su rivista]
Bassetti, C. L. A.; Kallweit, U.; Vignatelli, L.; Plazzi, G.; Lecendreux, M.; Baldin, E.; Dolenc-Groselj, L.; Jennum, P.; Khatami, R.; Manconi, M.; Mayer, G.; Partinen, M.; Pollmacher, T.; Reading, P.; Santamaria, J.; Sonka, K.; Dauvilliers, Y.; Lammers, G. J.

Background and purpose: 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 (EDS) in adults–scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults–SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children–scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (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.

2021 - European guideline and expert statements on the management of narcolepsy in adults and children [Articolo su rivista]
Bassetti, C. L. A.; Kallweit, U.; Vignatelli, L.; Plazzi, G.; Lecendreux, M.; Baldin, E.; Dolenc-Groselj, L.; Jennum, P.; Khatami, R.; Manconi, M.; Mayer, G.; Partinen, M.; Pollmacher, T.; Reading, P.; Santamaria, J.; Sonka, K.; Dauvilliers, Y.; Lammers, G. J.

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.

2021 - Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease [Articolo su rivista]
Gaig, Carles; Compta, Yaroslau; Heidbreder, Anna; Marti, Maria J; Titulaer, Maarten J; Crijnen, Yvette; Högl, Birgit; Lewerenz, Jan; Erro, María Elena; Garcia-Monco, Juan Carlos; Nigro, Pasquale; Tambasco, Nicola; Patalong-Ogiewa, Maja; Erdler, Marcus; Macher, Stefan; Berger-Sieczkowski, Evelyn; Höftberger, Romana; Geis, Christian; Hutterer, Markus; Milán-Tomás, Angela; Martin-Bastida, Antonio; Manzanares, Lydia Lopez; Quintas, Sonia; Höglinger, Günter U; Möhn, Nora; Schoeberl, Florian; Thaler, Franziska S; Asioli, Gian Maria; Provini, Federica; Plazzi, Giuseppe; Berganzo, Koldo; Blaabjerg, Morten; Brüggemann, Norbert; Farias, Tarsis; Ng, Chen Fei; Giordana, Caroline; Herrero-San Martín, Alejandro; Huebra, Lucio; Kotschet, Katya; Liendl, Herburg; Montojo, Teresa; Morata, Carlos; Perez, Jesus Perez; Puertas, Inmaculada; Seifert-Held, Thomas; Seitz, Caspar; Simabukuro, Mateus Mistieri; Tellez, Nieves; Villacieros-Álvarez, Javier; Willekens, Barbara; Sabater, Lidia; Iranzo, Alex; Cano, Joan Santamaria; Dalmau, Josep; Graus, Francesc

Background and Objectives Anti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease. Methods In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders. Results Seventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases. Discussion Movement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

2021 - How our dreams changed during the COVID-19 pandemic: Effects and correlates of dream recall frequency - a multinational study on 19,355 adults [Articolo su rivista]
Frankl, E.; Scarpelli, S.; Nadorff, M. R.; Bjorvatn, B.; Bolstad, C. J.; Chan, N. Y.; Chung, F.; Dauvilliers, Y.; Espie, C. A.; Inoue, Y.; Leger, D.; Macedo, T.; Matsui, K.; Merikanto, I.; Morin, C. M.; Mota-Rolim, S.; Partinen, M.; Penzel, T.; Plazzi, G.; Sieminski, M.; Wing, Y. K.; De Gennaro, L.; Holzinger, B.

Objective: Many have reported odd dreams during the pandemic. Given that dreams are associated with mental health, understanding these changes could provide crucial information about wellbeing during the pandemic. This study explored associations between COVID-19 and dream recall frequency (DRF), and related social, health, and mental health factors. Methods: We conducted a cross-sectional web survey of 19,355 individuals in 14 countries from May to July 2020. We collected data on COVID-19, mental health, sleep and DRF during the pandemic. We performed McNemar Tests to compare low (<3 nights per week) and high DRF (≥3 nights per week) before and during COVID-19 and to evaluate changes in sleep variables segmented by DRF. Chi-square tests were conducted to compare characteristics between low and high DRF. Logistic regression analyses were conducted to examine associations between various independent variables and DRF. Results: Reports of high DRF during the pandemic were higher than before the pandemic (P<0.001). Female gender (aOR=1.25, 95% CI 1.10–1.41), nightmares (aOR=4.22, 95% CI 3.45–5.17), sleep talking (aOR= 2.36, 1.73–3.23), sleep maintenance problems (aOR=1.34, 95% CI 1.15–1.56), symptoms of REM sleep behavior disorder (RBD; aOR=1.24, 95% CI 1.09–1.41) and repeated disturbing thoughts (posttraumatic stress disorder (PTSD) symptoms) were associated with high DRF. Age group 55–64 years (aOR=0.69, 95% CI 0.58–0.83) reported less high DRF than younger participants. Unadjusted OR showed associations between depression, anxiety, and DRF; however, in adjusted regression depression (aOR= 0.71, 0.59–0.86) and anxiety (aOR=0.79, 95% CI 0.66–0.94) were negatively associated with high DRF. Conclusion and Relevance: DRF was higher than pre-pandemic levels across four continents. DRF was associated with gender and parasomnias like nightmares and RBD symptoms, sleep maintenance problems, PTSD symptoms and negatively associated with depression and anxiety. The results implicate that COVID-19 is reflected in our dreams as an expression of the emotional intensity of the pandemic.

2021 - Hypothalamus and amygdala functional connectivity at rest in narcolepsy type 1 [Articolo su rivista]
Ballotta, D.; Talami, F.; Pizza, F.; Vaudano, A. E.; Benuzzi, F.; Plazzi, G.; Meletti, S.

Introduction: functional and structural MRI studies suggest that the orexin (hypocretin) deficiency in the dorso-lateral hypothalamus of narcoleptic patients would influence both brain metabolism and perfusion and would cause reduction in cortical grey matter. Previous fMRI studies have mainly focused on cerebral functioning during emotional processing. The aim of the present study was to explore the hemodynamic behaviour of spontaneous BOLD fluctuation at rest in patients with Narcolepsy type 1 (NT1) close to disease onset. Methods: Fifteen drug naïve children/adolescents with NT1 (9 males; mean age 11.7 ± 3 years) and fifteen healthy children/adolescents (9 males; mean age 12.4 ± 2.8 years) participated in an EEG-fMRI study in order to investigate the resting-state functional connectivity of hypothalamus and amygdala. Functional images were acquired on a 3 T system. Seed-based functional connectivity analyses were performed using SPM12. Regions of Interest were the lateral hypothalamus and the amygdala. Results: compared to controls, NT1 patients showed decreased functional connectivity between the lateral hypothalamus and the left superior parietal lobule, the hippocampus and the parahippocampal gyrus. Decreased functional connectivity was detected between the amygdala and the post-central gyrus and several occipital regions, whereas it was increased between the amygdala and the inferior frontal gyrus, claustrum, insula, and putamen. Conclusion: in NT1 patients the abnormal connectivity between the hypothalamus and brain regions involved in memory consolidation during sleep, such as the hippocampus, may be linked to the loss of orexin containing neurons in the dorsolateral hypothalamus. Moreover, also functional connectivity of the amygdala seems to be influenced by the loss of orexin-containing neurons. Therefore, we can hypothesize that dysfunctional interactions between regions subserving the maintenance of arousal, memory and emotional processing may contribute to the main symptom of narcolepsy.

2021 - Increased chin muscle tone during all sleep stages in children taking selective serotonin reuptake inhibitor antidepressants and in children with narcolepsy type 1 [Articolo su rivista]
Ferri, R.; Mogavero, M. P.; Bruni, O.; Plazzi, G.; Schenck, C. H.; Delrosso, L. M.

Study Objectives: To assess if selective serotonin reuptake inhibitor (SSRI) antidepressants are able to modify the chin electromyogram (EMG) tone during sleep also in children. Methods: Twenty-three children and adolescents (12 girls, mean age 14.1 years, SD 2.94) under therapy with antidepressant for their mood disorder were consecutively recruited and had a PSG recording. Twenty-one were taking were taking SSRI and treatment duration was 2-12 months. An age- and sex matched group of 33 control children (17 girls, mean age 14.2 years, SD 2.83) and 24 children with narcolepsy type 1 (12 girls, mean age 13.7 years, SD 2.80) were also included. The Atonia Index was then computed for each NREM sleep stage and for REM sleep, also all EMG activations were counted. Results: Atonia Index in all sleep stages was found to be significantly reduced in children with narcolepsy followed by the group taking SSRI antidepressants and the number of EMG activations was also increased in both groups. Fluoxetine, in particular, was found to be significantly associated with reduced Atonia index during NREM sleep stages N1, N2, and N3, and with an increased number of EMG activations/hour during sleep stage N3. Conclusions: Similarly to adults, SSRI antidepressants are able to modify the chin EMG tone in children during REM sleep, as well as during NREM sleep stages. Different pharmacological properties of the different SSRI might explain the differential effect on chin tone during sleep found in this study.

2021 - Increased Serum Prolactin and Excessive Daytime Sleepiness: An Attempt of Proof-of-Concept Study [Articolo su rivista]
Mogavero, M. P.; Cosentino, F. I. I.; Lanuzza, B.; Tripodi, M.; Lanza, G.; Arico, D.; Delrosso, L. M.; Pizza, F.; Plazzi, G.; Ferri, R.

The objectives of this study were: (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 subjects were retrieved: 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.

2021 - Insomnia, anxiety, and depression during the COVID-19 pandemic: an international collaborative study [Articolo su rivista]
Morin, C. M.; Bjorvatn, B.; Chung, F.; Holzinger, B.; Partinen, M.; Penzel, T.; Ivers, H.; Wing, Y. K.; Chan, N. Y.; Merikanto, I.; Mota-Rolim, S.; Macedo, T.; De Gennaro, L.; Leger, D.; Dauvilliers, Y.; Plazzi, G.; Nadorff, M. R.; Bolstad, C. J.; Sieminski, M.; Benedict, C.; Cedernaes, J.; Inoue, Y.; Han, F.; Espie, C. A.

Importance and study objective: The COVID-19 pandemic has produced unprecedented changes in social, work, and leisure activities, which all have had major impact on sleep and psychological well-being. This study documented the prevalence of clinical cases of insomnia, anxiety, and depression and selected risk factors (COVID-19, confinement, financial burden, social isolation) during the first wave of the pandemic in 13 countries throughout the world. Design and participants: International, multi-center, harmonized survey of 22 330 adults (mean age = 41.9 years old, range 18–95; 65.6% women) from the general population in 13 countries and four continents. Participants were invited to complete a standardized web-based survey about sleep and psychological symptoms during the first wave of the COVID-19 pandemic from May to August 2020. Results: Clinical insomnia symptoms were reported by 36.7% (95% CI, 36.0–37.4) of respondents and 17.4% (95% CI, 16.9–17.9) met criteria for a probable insomnia disorder. There were 25.6% (95% CI, 25.0–26.2) with probable anxiety and 23.1% (95% CI, 22.5–23.6) with probable depression. Rates of insomnia symptoms (>40%) and insomnia disorder (>25%) were significantly higher in women, younger age groups, and in residents of Brazil, Canada, Norway, Poland, USA, and United Kingdom compared to residents from Asian countries (China and Japan, 8% for disorder and 22%–25% for symptoms) (all Ps < 0.01). Proportions of insomnia cases were significantly higher among participants who completed the survey earlier in the first wave of the pandemic relative to those who completed it later. Risks of insomnia were higher among participants who reported having had COVID-19, who reported greater financial burden, were in confinement for a period of four to five weeks, and living alone or with more than five people in same household. These associations remained significant after controlling for age, sex, and psychological symptoms. Conclusion and relevance: Insomnia, anxiety, and depression were very prevalent during the first wave of the COVID-19 pandemic. Public health prevention programs are needed to prevent chronicity and reduce long-term adverse outcomes associated with chronic insomnia and mental health problems.

2021 - International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders [Articolo su rivista]
Palagini, L.; Manni, R.; Aguglia, E.; Amore, M.; Brugnoli, R.; Bioulac, S.; Bourgin, P.; Micoulaud Franchi, J. -A.; Girardi, P.; Grassi, L.; Lopez, R.; Mencacci, C.; Plazzi, G.; Maruani, J.; Minervino, A.; Philip, P.; Royant Parola, S.; Poirot, I.; Nobili, L.; Biggio, G.; Schroder, C. M.; Geoffroy, P. A.

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders. Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method. Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders. Conclusion: The administration of prolonged release melatonin at 2–10 mg, 1–2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at <1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders.

2021 - Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci [Articolo su rivista]
Ambati, Aditya; Hillary, Ryan; Leu-Semenescu, Smaranda; Ollila, Hanna M; Lin, Ling; During, Emmanuel H; Farber, Neal; Rico, Thomas J; Faraco, Juliette; Leary, Eileen; Goldstein-Piekarski, Andrea N; Huang, Yu-Shu; Han, Fang; Sivan, Yakov; Lecendreux, Michel; Dodet, Pauline; Honda, Makoto; Gadoth, Natan; Nevsimalova, Sona; Pizza, Fabio; Kanbayashi, Takashi; Peraita-Adrados, Rosa; Leschziner, Guy D; Hasan, Rosa; Canellas, Francesca; Kume, Kazuhiko; Daniilidou, Makrina; Bourgin, Patrice; Rye, David; Vicario, José L; Hogl, Birgit; Hong, Seung Chul; Plazzi, Giuseppe; Mayer, Geert; Landtblom, Anne Marie; Dauvilliers, Yves; Arnulf, Isabelle; Mignot, Emmanuel Jean-Marie

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 * 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R 2 = 0.15; P < 2.0 * 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

2021 - Maladaptive Daydreaming in an Adult Italian Population During the COVID-19 Lockdown [Articolo su rivista]
Musetti, A.; Franceschini, C.; Pingani, L.; Freda, M. F.; Saita, E.; Vegni, E.; Zenesini, C.; Quattropani, M. C.; Lenzo, V.; Margherita, G.; Lemmo, D.; Corsano, P.; Borghi, L.; Cattivelli, R.; Plazzi, G.; Castelnuovo, G.; Somer, E.; Schimmenti, A.

During the COVID-19 outbreak, individuals with or without mental disorders may resort to dysfunctional psychological strategies that could trigger or heighten their emotional distress. The current study aims to explore the links between maladaptive daydreaming (MD, i.e., a compulsive fantasy activity associated with distress and psychological impairment), psychological symptoms of depression, anxiety, and negative stress, and COVID-19-related variables, such as changes in face-to-face and online relationships, during the COVID-19 lockdown in Italy. A total of 6,277 Italian adults completed an online survey, including socio-demographic variables, COVID-19 related information, the 16-item Maladaptive Daydreaming Scale (MDS-16), and Depression, Anxiety, and Stress Scales-21 Items (DASS-21). Based on an empirically derived cut-off score, 1,082 participants (17.2%) were identified as probable maladaptive daydreamers (MDers). A binary logistic regression revealed that compared to controls, probable MDers reported that during the COVID-19 lockdown they experienced higher levels of anxiety and depression, decreased online social relationships, and, surprisingly, stable or increased face-to-face social relationships. Given the peculiar characteristics of the pandemic context, these findings suggest that the exposure to the risk of contagion had probably exacerbated the tendency of probable MDers to lock themselves inside their mental fantasy worlds, which in turn may have contributed to further estrangement from online social relationships and support, thus worsening their emotional distress.

2021 - Myasthenic or cataplectic facies? Ice pack test response in paediatric type 1 narcolepsy [Articolo su rivista]
Pensato, U.; Pizza, F.; Plazzi, G.

2021 - Narcolepsy type 1 features across the life span: age impact on clinical and polysomnographic phenotype [Articolo su rivista]
Lividini, Althea; Pizza, Fabio; Filardi, Marco; Vandi, Stefano; Ingravallo, Francesca; Antelmi, Elena; Bruni, Oliviero; Ilaria Cosentino, Filomena Irene; Ferri, Raffaele; Guarnieri, Biancamaria; Marelli, Sara; Ferini-Strambi, Luigi; Romigi, Andrea; Bonanni, Enrica; Maestri, Michelangelo; Terzaghi, Michele; Manni, Raffaele; Plazzi, Giuseppe

STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a chronic neurological disorder typically arising during adolescence and young adulthood. Recent studies demonstrated that NT1 presents with age-specific features, especially in children. With this study we aimed to describe and to compare the clinical pictures of NT1 in different age groups.METHODS: In this cross-sectional, multicenter study, 106 untreated NT1 patients, enrolled at the time of diagnosis, underwent clinical evaluation, a semi-structured interview (including the Epworth Sleepiness Scale - ESS), nocturnal video-polysomnography and the Multiple Sleep Latency Test (MSLT). Patients were enrolled in order to establish five age-balanced groups (childhood, adolescence, adulthood, middle-aged and seniors).RESULTS: The ESS score showed a significant increase with age, while self-reported diurnal total sleep time was lower in elderly and young adults, with the latter also complaining of automatic behaviors in more than 90% of cases. Children reported the cataplexy attacks to be more frequent (>1/day in 95% of cases). "Recalling an emotional event", "meeting someone unexpectedly", "stress" and "anger" were more frequently reported in adult and elderly patients as possible triggers of cataplexy. Neurophysiological data showed a higher number of SOREMPs on the MSLT in adolescents compared to senior patients and an age-progressive decline in sleep efficiency.CONCLUSIONS: Daytime sleepiness, cataplexy features and triggers, and nocturnal sleep structure showed age-related difference in NT1 patients; this variability may contribute to diagnostic delay and misdiagnosis.

2021 - Neurofilament light chain and α-synuclein RT-QuIC as differential diagnostic biomarkers in parkinsonisms and related syndromes [Articolo su rivista]
Quadalti, C.; Calandra-Buonaura, G.; Baiardi, S.; Mastrangelo, A.; Rossi, M.; Zenesini, C.; Giannini, G.; Candelise, N.; Sambati, L.; Polischi, B.; Plazzi, G.; Capellari, S.; Cortelli, P.; Parchi, P.

Neurofilament light chain (NfL) and α-synuclein oligomeric seeds (α-syn-s) are promising biomarkers for patients with parkinsonism. We assessed their performance in discriminating Parkinson disease (PD) from atypical parkinsonisms (APDs) and evaluated the association between NfL levels and clinical measures of disease severity. We measured NfL in cerebrospinal fluid (CSF) and/or plasma by immunoassays and α-syn-s in CSF by real-time quaking-induced conversion (RT-QuIC) in patients with PD (n = 153), multiple system atrophy (MSA) (n = 80), progressive supranuclear palsy/cortico-basal syndrome (PSP/CBS) (n = 58), dementia with Lewy bodies (n = 64), isolated REM-sleep behaviour disorder (n = 19), and isolated autonomic failure (n = 30). Measures of disease severity included disease duration, UPDRS-III score, Hoehn and Yahr stage, orthostatic hypotension, MMSE score, and CSF amyloid-beta profile. Both CSF NfL (cNfL) and plasma NfL (pNfL) levels were markedly elevated in APDs, and allowed differentiation with PD (vs. APDs, cNfL AUC 0.96; pNfL AUC 0.95; vs. MSA cNfL AUC 0.99; pNfL AUC 0.97; vs. PSP/CBS cNfL AUC 0.94; pNfL AUC 0.94). RT-QuIC detected α-syn-s in 91.4% of PD, but only 2.5% of APDs (all MSA). In PD/PDD, motor scales significantly correlated with cNfL levels. Although pNfL and both cNfL and α-syn-s accurately distinguished PD from APDs, the combined assessment of CSF markers provided a higher diagnostic value (PD vs. APDs AUC 0.97; vs. MSA AUC 0.97; vs. PSP/CBS AUC 0.99) than RT-QuIC alone (p = 0.047 vs. APDs; p = 0.002 vs MSA; p = 0.007 vs PSP/CBS), or cNfL alone (p = 0.011 vs. APDs; p = 0.751 vs MSA; p = 0.0001 vs. PSP/CBS). The results support the use of these assays in specialised clinics.

2021 - Neuronal surface antibodies are common in children with narcolepsy and active movement disorders [Articolo su rivista]
Giannoccaro, M. P.; Pizza, F.; Jacobson, L.; Liguori, R.; Plazzi, G.; Vincent, A.

2021 - New 2013 incidence peak in childhood narcolepsy: more than vaccination? [Articolo su rivista]
Zhang, Z.; Gool, J. K.; Fronczek, R.; Dauvilliers, Y.; Bassetti, C. L. A.; Mayer, G.; Plazzi, G.; Pizza, F.; Santamaria, J.; Partinen, M.; Overeem, S.; Peraita-Adrados, R.; da Silva, A. M.; Sonka, K.; Del Rio-Villegas, R.; Heinzer, R.; Wierzbicka, A.; Young, P.; Hogl, B.; Manconi, M.; Feketeova, E.; Mathis, J.; Paiva, T.; Canellas, F.; Lecendreux, M.; Baumann, C. R.; Lammers, G. J.; Khatami, R.

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

2021 - Nocturnal eye movements in patients with idiopathic rapid eye movement sleep behaviour disorder and patients with Parkinson’s disease [Articolo su rivista]
Christensen, J. A. E.; Cesari, M.; Pizza, F.; Antelmi, E.; Frandsen, R. A. V.; Plazzi, G.; Jennum, P.

Patients with idiopathic rapid-eye-movement (REM) sleep behaviour disorder (iRBD) have a high risk of converting into manifest α-synucleinopathies. Eye movements (EMs) are controlled by neurons in the lower brainstem, midbrain and frontal areas, and may be affected by the early neurodegenerative process seen in iRBD. Studies have reported impairment of the oculomotor function in patients with Parkinson's disease (PD) during wakefulness, but no studies have investigated EMs during sleep. We aimed to evaluate nocturnal EMs in iRBD and PD, hypothesizing that these patients present abnormal EM distribution during sleep. Twenty-eight patients with periodic limb movement disorder (PLMD), 24 iRBD, 23 PD without RBD (PDwoRBD), 29 PD and RBD (PDwRBD) and 24 controls were included. A validated EM detector automatically identified EM periods between lights off and on. The EM coverage was computed as the percentage of time containing EMs during stable wake after lights off, N1, N2, N3 and REM sleep. Between-group comparisons revealed that PDwRBD had significantly less EM coverage during wake and significantly higher EM coverage during N2 compared to controls and PLMD patients. PDwoRBD showed significantly less EM coverage during wake compared to controls and higher EM coverage during N2 compared to controls and PLMD. Finally, iRBD showed less coverage of EM during wake compared to controls. The same trend was observed between iRBD and controls in N2 but was not significant. The different profiles of EM coverage in iRBD and PD with/without RBD may mirror different stages of central nervous system involvement across neurodegenerative disease progression.

2021 - Non-continuous positive airway pressure treatment options in obstructive sleep apnoea: A pathophysiological perspective [Articolo su rivista]
Bosi, M.; Incerti Parenti, S.; Sanna, A.; Plazzi, G.; De Vito, A.; Alessandri-Bonetti, G.

The phenotyping of the pathophysiology of obstructive sleep apnoea (OSA) lies at the core of tailored treatments and it is one of the most debated topics in sleep medicine research. Recent sophisticated techniques have broadened the horizon for gaining insight into the variability of the endotypic traits in patients with OSA which account for the heterogeneity in the clinical presentation of the disease and consequently, in the outcome of treatment. However, the implementation of these concepts into clinical practice is still a major challenge for both researchers and clinicians in order to develop tailored therapies targeted to specific endotypic traits that contribute to OSA in each individual patient. This review summarizes available scientific evidence in order to point out the links between endotypic traits (pharyngeal airway collapsibility, upper airway neuromuscular compensation, loop gain and arousal threshold) and the most common non-continuous positive airway pressure (CPAP) treatment options for OSA (mandibular advancement device, upper airway surgery, medication therapy, positional therapy) and to clarify to what extent endotypic traits could help to better predict the success of these therapies. A narrative guide is provided; current design limitations and future avenues of research are discussed, with clinical and research perspectives.

2021 - Novel Associations of BST1 and LAMP3 with Rapid Eye Movement Sleep Behavior Disorder [Articolo su rivista]
Mufti, Kheireddin; Yu, Eric; Rudakou, Uladzislau; Krohn, Lynne; Ruskey, Jennifer A; Asayesh, Farnaz; Laurent, Sandra B; Spiegelman, Dan; Arnulf, Isabelle; Hu, Michele T M; Montplaisir, Jacques Y; Gagnon, Jean-François; Desautels, Alex; Dauvilliers, Yves; Gigli, Gian Luigi; Valente, Mariarosaria; Janes, Francesco; Bernardini, Andrea; Högl, Birgit; Stefani, Ambra; Holzknecht, Evi; Sonka, Karel; Kemlink, David; Oertel, Wolfgang; Janzen, Annette; Plazzi, Giuseppe; Antelmi, Elena; Figorilli, Michela; Puligheddu, Monica; Mollenhauer, Brit; Trenkwalder, Claudia; Sixel-Döring, Friederike; De Cock, Valérie Cochen; Monaca, Christelle Charley; Heidbreder, Anna; Ferini-Strambi, Luigi; Dijkstra, Femke; Viaene, Mineke; Abril, Beatriz; Boeve, Bradley F; Trempe, Jean-François; Rouleau, Guy A; Postuma, Ronald B; Gan-Or, Ziv

To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).

2021 - Onset of narcolepsy type 1 in a paraneoplastic encephalitis associated with a thymic seminoma [Articolo su rivista]
Rossi, S.; Asioli, G. M.; Rizzo, G.; Sallemi, G.; Moresco, M.; Franceschini, C.; Pizza, F.; Plazzi, G.

Narcolepsy type 1 results from probable autoimmune disruption of hypothalamic hypocretinergic neurons. Secondary narcolepsy can occur as a result of other conditions affecting the central nervous system, including limbic paraneoplastic encephalitis. We report the case of a 19-year-old patient presenting with acute-onset diurnal hypersomnolence, hyperphagia, sexual dysfunction, and psychiatric disturbances. Further investigations revealed a limbic paraneoplastic encephalitis associated with mediastinal thymic seminoma. Tumor removal and immunosuppressive treatment resulted in a partial benefit on psychiatric disturbances but did not improve daytime sleepiness. A comprehensive sleep assessment led to the diagnosis of secondary narcolepsy type 1 with reduced cerebrospinal fluid hypocretin-1 levels and revealed the presence of the HLA DQB1*0602 allele, typically associated with idiopathic narcolepsy, for which we hypothesize a possible immunopathogenic role. Sodium oxybate was successfully administered. Narcolepsy is often overlooked in patients with limbic paraneoplastic encephalitis. A prompt assessment and an adequate symptomatic treatment can improve the disease burden. CITATION: Rossi S, Asioli GM, Rizzo G, et al. Onset of narcolepsy type 1 in a paraneoplastic encephalitis associated with a thymic seminoma. J Clin Sleep Med. 2021;17(12):2557-2560.

2021 - Pandemic nightmares: Effects on dream activity of the COVID-19 lockdown in Italy [Articolo su rivista]
Scarpelli, S.; Alfonsi, V.; Mangiaruga, A.; Musetti, A.; Quattropani, M. C.; Lenzo, V.; Freda, M. F.; Lemmo, D.; Vegni, E.; Borghi, L.; Saita, E.; Cattivelli, R.; Castelnuovo, G.; Plazzi, G.; De Gennaro, L.; Franceschini, C.

COVID-19 has critically impacted the world. Recent works have found substantial changes in sleep and mental health during the COVID-19 pandemic. Dreams could give us crucial information about people's well-being, so here we have directly investigated the consequences of lockdown on the oneiric activity in a large Italian sample: 5,988 adults completed a web-survey during lockdown. We investigated sociodemographic and COVID-19-related information, sleep quality (by the Medical Outcomes Study-Sleep Scale), mental health (by the Depression, Anxiety, and Stress Scales), dream and nightmare frequency, and related emotional aspects (by the Mannheim Dream Questionnaire). Comparisons between our sample and a population-based sample revealed that Italians are having more frequent nightmares and dreams during the pandemic. A multiple logistic regression model showed the predictors of high dream recall (young age, female gender, not having children, sleep duration) and high nightmare frequency (young age, female gender, modification of napping, sleep duration, intrasleep wakefulness, sleep problem index, anxiety, depression). Moreover, we found higher emotional features of dream activity in workers who have stopped working, in people who have relatives/friends infected by or who have died from COVID-19 and in subjects who have changed their sleep habits. Our findings point to the fact that the predictors of high dream recall and nightmares are consistent with the continuity between sleep mentation and daily experiences. According to the arousal-retrieval model, we found that poor sleep predicts a high nightmare frequency. We suggest monitoring dream changes during the epidemic, and also considering the implications for clinical treatment and prevention of mental and sleep disorders.

2021 - Parental quality of life and involvement in intervention for children or adolescents with autism spectrum disorders: A systematic review [Articolo su rivista]
Musetti, A.; Manari, T.; Dioni, B.; Raffin, C.; Bravo, G.; Mariani, R.; Esposito, G.; Dimitriou, D.; Plazzi, G.; Franceschini, C.; Corsano, P.

Previous research has examined several parental, child-related, and contextual factors associated with parental quality of life (QoL) among parents with a child or an adolescent with autism spectrum disorders (ASD); however, no systematic review has examined the relationship between parental QoL and parental involvement in intervention. To fill this gap, a systematic review was conducted using four electronic databases and checked reference lists of retrieved studies. Records were included in the systematic review if they presented original data, assessed parental QoL, and involvement in intervention for children or adolescents with ASD, were published in peer-reviewed journals between 2000 and 2020, and were written in English. Among the 96 screened full-texts, 17 articles met the eligibility criteria. The selected studies included over 2000 parents of children or adolescents with ASD. Three categories of parental involvement (i.e., none, indirect, direct) were identified, which varied across studies, although most had direct parental involvement. The results from this review show that increased parental involvement in the intervention for children or adolescents with ASD may be one way to promote their QoL. However, further research specifically focused on parental involvement during the intervention for children and adolescents with ASD is warranted.

2021 - Persistence of the effects of the covid-19 lockdown on sleep: A longitudinal study [Articolo su rivista]
Gorgoni, M.; Scarpelli, S.; Mangiaruga, A.; Alfonsi, V.; Bonsignore, M. R.; Fanfulla, F.; Ferini-Strambi, L.; Nobili, L.; Plazzi, G.; De Gennaro, L.

The effects of the COVID-19 pandemic on sleep have been widely documented, but longitudinal evaluations during different phases of the “COVID-19 era” are needed to disentangle the specific consequences of the r145estrictive measures on sleep variables. The aim of this study was to assess the immediate effect of the lockdown’s end on sleep and sleep-related dimensions in an Italian sample, also considering the stress and depressive symptoms. We used an online survey to longitudinally collect data on sociodemographic, environmental, clinical, sleep, and sleep-related variables in two time points: during and immediately after the lockdown. The final sample included 102 participants. The large prevalence of poor sleep quality, clinically relevant pre-sleep arousal, and depressive symptoms, as well as poor sleep quality and pre-sleep arousal score observed during the lockdown, remained stable after its end. On the other hand, the prevalence of moderate-to-severe event-related stress and intrusive symptom scores exhibited a drastic reduction after the end of home confinement. Both bedtime and rise time were anticipated after the lockdown, while sleep quality exhibited only a trend of post-lockdown sleep disturbance reduction. Our findings point to a reduced stress level (specific for the intrusive symptomatology) after the end of the lockdown and persistence of sleep problems, suggesting two non-mutually exclusive hypotheses: (a) the strict restrictive measures are not the main cause of sleep problems during the pandemic and (b) home confinement induces long-lasting effects on sleep observable after its end, and a longer period of time might be needed to observe an improvement.

2021 - Pre-sleep arousal and sleep quality during the COVID-19 lockdown in Italy [Articolo su rivista]
Gorgoni, M.; Scarpelli, S.; Mangiaruga, A.; Alfonsi, V.; Bonsignore, M. R.; Fanfulla, F.; Ferini-Strambi, L.; Nobili, L.; Plazzi, G.; De Gennaro, L.; Arnaldi, D.; Bonanni, E.; Bonetti, G. A.; Castronovo, C.; Maestri, M.; Garbarino, S.; Guarnieri, B.; Manni, R.; Palagini, L.; Puligheddu, M.; Ferri, R.; Silvani, A.; Vicini, C.

Objective: The COVID-19 pandemic has strongly affected daily habits and psychological wellbeing, and many studies point to large modifications in several sleep and sleep-related domains. Nevertheless, pre-sleep arousal during the pandemic has been substantially overlooked. Since hyperarousal represents one of the main factors for the development and the perpetuation of chronic insomnia disorder, the assessment of variables associated with high levels of pre-sleep arousal during the pandemic is clinically relevant. The study aimed to assess the prevalence and predictors of perceived sleep quality and pre-sleep arousal in an Italian sample during the COVID-19 lockdown. Methods: We used an online survey to collect self-reported sociodemographic, environmental, clinical, sleep, and sleep-related data. Our final sample included 761 participants. Results: Beyond a high frequency of poor sleep quality, depressive and stress symptoms, our results show that almost half of the sample suffered from clinically relevant levels of at least one component (ie, cognitive, somatic) of pre-sleep arousal. Subjects with greater pre-sleep arousal exhibited poorer sleep quality. Also, sleep quality was strongly associated with somatic and cognitive pre-sleep arousal. Regarding the predictors of sleep and sleep-related measures, depressive and event-related stress symptoms were the main factors associated with both poor sleep quality and pre-sleep arousal components. Moreover, specific sociodemographic and environmental variables were uniquely related to sleep quality, cognitive or somatic pre-sleep arousal. Conclusions: These findings suggest that the assessment of specific sleep-related factors (ie, pre-sleep arousal), together with more global measures of sleep quality, may be crucial to depict the complex impact of the pandemic on sleep, and to help prevent and counteract the spread of insomnia symptoms.

2021 - Pre-treatment of blood samples reveal normal blood hypocretin/orexin signal in narcolepsy type 1 [Articolo su rivista]
Ægidius, Helene M; Kruse, Lars; Christensen, Gitte L; Lorentzen, Marc P; Jørgensen, Niklas R; Moresco, Monica; Pizza, Fabio; Plazzi, Giuseppe; Jennum, Poul J; Kornum, Birgitte R

The hypocretin/orexin system regulates arousal through central nervous system mechanisms and plays an important role in sleep, wakefulness and energy homeostasis. It is unclear whether hypocretin peptides are also present in blood due to difficulties in measuring reliable and reproducible levels of the peptides in blood samples. Lack of hypocretin signalling causes the sleep disorder narcolepsy type 1, and low concentration of cerebrospinal fluid hypocretin-l/oreadn-A peptide is a hallmark of the disease. This measurement has high diagnostic value, but performing a lumbar puncture is not without discomfort and possible complications for the patient. A blood-based test to assess hypocretin-1 deficiency would therefore be of obvious benefit. We here demonstrate that heating plasma or scrum samples to 65 degrees C for 30 min at pH 8 significantly increases hypocretin-1 immunoreactivity enabling stable and reproducible measurement of hypocretin-1 in blood samples. Specificity of the signal was verified by high-performance liquid chromatography and by measuring blood samples from mice lacking hypocretin. Unspecific background signal in the assay was high. Using our method, we show that hypocretin-1 immunoreactivity in blood samples from narcolepsy type 1 patients does not differ from the levels detected in control samples. The data presented here suggest that hypocretin-1 is present in the blood stream in the low picograms per millilitres range and that peripheral hypocretin-1 concentrations are unchanged in narcolepsy type 1.

2021 - Psychometric properties of the Sleep Hygiene Index in a large Italian community sample [Articolo su rivista]
Zagaria, A.; Ballesio, A.; Musetti, A.; Lenzo, V.; Quattropani, M. C.; Borghi, L.; Margherita, G.; Saita, E.; Castelnuovo, G.; Filosa, M.; Palagini, L.; Plazzi, G.; Lombardo, C.; Franceschini, C.

Objective/background: Poor sleep hygiene is considered an exacerbating and perpetuating factor of sleep disturbances and is also associated with poor mental health. The Sleep Hygiene Index (SHI) is a self-report measure assessing adherence to sleep hygiene practices. The aim of this study was to estimate the psychometric properties of the SHI in an Italian representative sample of the general population, following a formative measurement approach. Patients/methods: Participants (n = 6276; M = 33.62, SD = 13.45) completed the SHI alongside measures of sleep disturbance, depression, anxiety, and stress. To consider the item formative nature, sets of item-composites weighted by means of canonical correlation analysis was created and a confirmatory factor analysis (CFA) was implemented. Factorial invariance tests were computed considering both presence of sleep problems and presence of emotional distress symptoms as grouping variables. Results and conclusions: CFA confirmed the unidimensional structure of SHI. Internal consistency was acceptable (ω = 0.752). Test-retest reliability at 8–10 months presented an ICC of 0.666. SHI significantly correlated with sleep, depression, anxiety and stress symptoms (r range from 0.358 to 0.500). Configural and metric invariance were reached for both grouping variables. Partial scalar invariance was obtained only across emotional distress groups. People with emotional symptoms reported higher latent means on the sleep hygiene dimension. Findings support the validity and reliability of the Italian version of the SHI. Importantly, the SHI showed robust psychometric properties both in healthy individuals and in individual reporting mental health symptoms. Thus, it is advisable to use this version of the SHI in both research and clinical practice.

2021 - REM Sleep Behavior Disorder in Children With Type 1 Narcolepsy Treated With Sodium Oxybate [Articolo su rivista]
Antelmi, Elena; Filardi, Marco; Pizza, Fabio; Vandi, Stefano; Moresco, Monica; Franceschini, Christian; Tinazzi, Michele; Ferri, Raffaele; Plazzi, Giuseppe

To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1).

2021 - REM sleep behavior disorder: Mimics and variants [Articolo su rivista]
Antelmi, E.; Lippolis, M.; Biscarini, F.; Tinazzi, M.; Plazzi, G.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia with dream-enactment behaviors occurring during REM sleep and associated with the lack of the physiological REM sleep muscle atonia. It can be isolated and secondary to other neurological or medical conditions. Isolated RBD heralds in most cases a neurodegenerative condition due to an underlying synucleinopathy and consequently its recognition is crucial for prognostic implications. REM sleep without atonia on polysomnography is a mandatory diagnostic criterion. Different conditions may mimic RBD, the most frequent being obstructive sleep apnea during sleep, non-REM parasomnia, and sleep-related hypermotor epilepsy. These diseases might also be comorbid with RBD, challenging the evaluation of disease severity, the treatment choices and the response to treatment evaluation. Video-PSG is the gold standard for a correct diagnosis and will distinguish between different or comorbid sleep disorders. Careful history taking together with actigraphy may give important clues for the differential diagnosis. The extreme boundaries of RBD might also be seen in more severe and complex conditions like status dissociatus or in the sleep disorders’ scenario of anti IgLON5 disease, but in the latter both clinical and neurophysiological features will differ. A step-by-step approach is suggested to guide the differential diagnosis.

2021 - Reviewing the clinical implications of treating narcolepsy as an autoimmune disorder [Articolo su rivista]
Giannoccaro, M. P.; Liguori, R.; Plazzi, G.; Pizza, F.

Narcolepsy type 1 (NT1) is a lifelong sleep disorder, primarily characterized clinically by excessive daytime sleepiness and cataplexy and pathologically by the loss of hypocretinergic neurons in the lateral hypothalamus. Despite being a rare disorder, the NT1-related burden for patients and society is relevant due to the early onset and chronic nature of this condition. Although the etiology of narcolepsy is still unknown, mounting evidence supports a central role of autoimmunity. To date, no cure is available for this disorder and current treatment is symptomatic. Based on the hypothesis of the autoimmune etiology of this disease, immunotherapy could possibly represent a valid therapeutic option. However, contrasting and limited results have been provided so far. This review discusses the evidence supporting the use of immunotherapy in narcolepsy, the outcomes obtained so far, current issues and future directions.

2021 - Searching for novel candidate biomarkers of rls in blood by proteomic analysis [Articolo su rivista]
Mondello, S.; Kobeissy, F. H.; Mechref, Y.; Zhao, J.; El Hayek, S.; Zibara, K.; Moresco, M.; Plazzi, G.; Cosentino, F. I. I.; Ferri, R.

Purpose: 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.

2021 - Sleep and daytime problems during the COVID-19 pandemic and effects of coronavirus infection, confinement and financial suffering: A multinational survey using a harmonised questionnaire [Articolo su rivista]
Partinen, M.; Holzinger, B.; Morin, C. M.; Espie, C.; Chung, F.; Penzel, T.; Benedict, C.; Bolstad, C. J.; Cedernaes, J.; Chan, R. N. Y.; Dauvilliers, Y.; De Gennaro, L.; Han, F.; Inoue, Y.; Matsui, K.; Leger, D.; Cunha, A. S.; Merikanto, I.; Mota-Rolim, S.; Nadorff, M.; Plazzi, G.; Schneider, J.; Sieminski, M.; Wing, Y. -K.; Bjorvatn, B.

Objectives Sleep is important for human health and well-being. No previous study has assessed whether the COVID-19 pandemic impacts sleep and daytime function across the globe. Methods This large-scale international survey used a harmonised questionnaire. Fourteen countries participated during the period of May-August 2020. Sleep and daytime problems (poor sleep quality, sleep onset and maintenance problems, nightmares, hypnotic use, fatigue and excessive sleepiness) occurring € before' and € during' the pandemic were investigated. In total, 25 484 people participated and 22 151 (86.9%) responded to the key parameters and were included. Effects of COVID-19, confinement and financial suffering were considered. In the fully adjusted logistic regression models, results (weighted and stratified by country) were adjusted for gender, age, marital status, educational level, ethnicity, presence of sleep problems before COVID-19 and severity of the COVID-19 pandemic in each country at the time of the survey. Results The responders were mostly women (64%) with a mean age 41.8 (SD 15.9) years (median 39, range 18-95). Altogether, 3.0% reported having had COVID-19; 42.2% reported having been in confinement; and 55.9% had suffered financially. All sleep and daytime problems worsened during the pandemic by about 10% or more. Also, some participants reported improvements in sleep and daytime function. For example, sleep quality worsened in about 20% of subjects and improved in about 5%. COVID-19 was particularly associated with poor sleep quality, early morning awakening and daytime sleepiness. Confinement was associated with poor sleep quality, problems falling asleep and decreased use of hypnotics. Financial suffering was associated with all sleep and daytime problems, including nightmares and fatigue, even in the fully adjusted logistic regression models. Conclusions Sleep problems, fatigue and excessive sleepiness increased significantly worldwide during the first phase of the COVID-19 pandemic. Problems were associated with confinement and especially with financial suffering.

2021 - Sleep Problems in Narcolepsy and the Role of Hypocretin/Orexin Deficiency [Capitolo/Saggio]
Mignot, E.; Zeitzer, J.; Pizza, F.; Plazzi, G.

Since its description in the 19th century, narcolepsy type 1 (NT1) has been considered as a model sleep disorder, and after the discovery of rapid eye movement (REM) sleep onset in the disorder, a gateway to understanding REM sleep. The discovery that NT1 is caused by hypocretin/orexin deficiency, together with neurochemical studies of this system, has helped to establish how this neuropeptide regulates the organization of sleep and wake in humans. Current analyses suggest that the main functions of the hypocretin/orexin system are (1) maintenance of wakefulness in the face of moderate sleep deprivation; (2) passive wake promotion, especially in the evening, driven by the circadian clock; (3) inhibition of REM sleep, with possible differential modulating effects on various subcomponents of the sleep-stage, explaining REM sleep dissociation events in NT1. Narcolepsy is also associated with an inability to consolidate sleep, a more complex phenotype that may result from secondary changes or be central to the role of hypocretin in coordinating the activity of other sleep- and wake-promoting systems. Novel technologies, such as the use of deep learning analysis of electroencephalographic signals, is revealing a complex pattern of sleep abnormalities in human narcolepsy that can be used diagnostically. The availability of novel devices measuring sleep 24 h per day also holds promise to provide new insights into how brain electrical activity and muscle tone are regulated by hypocretin.

2021 - Social jetlag changes during the COVID-19 pandemic as a predictor of insomnia - a multi-national survey study [Articolo su rivista]
Brandao, L. E. M.; Martikainen, T.; Merikanto, I.; Holzinger, B.; Morin, C. M.; Espie, C. A.; Bolstad, C. J.; Leger, D.; Chung, F.; Plazzi, G.; Dauvilliers, Y.; Matsui, K.; De Gennaro, L.; Sieminski, M.; Nadorff, M. R.; Chan, N. Y.; Wing, Y. K.; Mota-Rolim, S. A.; Inoue, Y.; Partinen, M.; Benedict, C.; Bjorvatn, B.; Cedernaes, J.

Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) - ie, the difference between sleep timing on working vs free days - and 2) symptoms of insomnia. Patients and Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example. Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23 - 54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL. Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms - even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity.

2021 - The association between high risk of sleep apnea, comorbidities, and risk of COVID-19: a population-based international harmonized study [Articolo su rivista]
Chung, F.; Waseem, R.; Pham, C.; Penzel, T.; Han, F.; Bjorvatn, B.; Morin, C. M.; Holzinger, B.; Espie, C. A.; Benedict, C.; Cedernaes, J.; Saaresranta, T.; Wing, Y. K.; Nadorff, M. R.; Dauvilliers, Y.; De Gennaro, L.; Plazzi, G.; Merikanto, I.; Matsui, K.; Leger, D.; Sieminski, M.; Mota-Rolim, S.; Inoue, Y.; Partinen, M.; Chan, N. Y.; Bolstad, C. J.; Schneider, J.; Huang, Y.; Fernandes, A.

Purpose: Obstructive sleep apnea (OSA) may increase the risk of severe COVID-19; however, the level of potential modulation has not yet been established. The objective of the study was to determine the association between high risk of OSA, comorbidities, and increased risk for COVID-19, hospitalization, and intensive care unit (ICU) treatment. Methods: We conducted a cross-sectional population-based web survey in adults in 14 countries/regions. The survey included sociodemographic variables and comorbidities. Participants were asked questions about COVID-19, hospitalization, and ICU treatment. Standardized questionnaire (STOP questionnaire for high risk of OSA) was included. Multivariable logistic regression was conducted adjusting for various factors. Results: Out of 26,539 respondents, 20,598 (35.4% male) completed the survey. Mean age and BMI of participants were 41.5 ± 16.0 years and 24.0 ± 5.0 kg/m2, respectively. The prevalence of physician-diagnosed OSA was 4.1% and high risk of OSA was 9.5%. We found that high risk of OSA (adjusted odds ratio (aOR) 1.72, 95% confidence interval (CI): 1.20, 2.47) and diabetes (aOR 2.07, 95% CI: 1.23, 3.48) were associated with reporting of a COVID-19 diagnosis. High risk for OSA (aOR 2.11, 95% CI: 1.10–4.01), being male (aOR: 2.82, 95% CI: 1.55–5.12), having diabetes (aOR: 3.93, 95% CI: 1.70–9.12), and having depression (aOR: 2.33, 95% CI: 1.15–4.77) were associated with increased risk of hospitalization or ICU treatment. Conclusions: Participants at high risk of OSA had increased odds of having COVID-19 and were two times more likely to be hospitalized or treated in ICU.

2020 - Autism Spectrum Disorder and Narcolepsy: A Possible Connection That Deserves to Be Investigated [Articolo su rivista]
Posar, A; Visconti, P; Blunda, V; Pizza, F; Plazzi, G.

Narcolepsy in childhood-adolescence is characterized by a high occurrence of psychiatric comorbidities. The most frequent psychiatric disorders reported in these patients are attention deficit/hyperactivity disorder, depression, anxiety disorder, and schizophrenia. However, narcolepsy can be associated also with introversion, sorrowfulness, feelings of inferiority, impaired affectivity modulation, emotional lability, irritability, aggressiveness, and poor attention, that have been pooled by some authors under a definition of "narcoleptic personality." Some aspects of this "narcoleptic personality," and in particular introversion, impaired affectivity modulation, irritability, and poor attention, partially overlap with the clinical features of the individuals with autism spectrum disorder, considering also those that are not regarded as core autism symptoms. Till now, in literature the number of cases affected by both narcolepsy and autism spectrum disorder (seven patients) has been clearly too small to demonstrate the presence of a pathogenetic link between these two conditions, but this possible connection has not yet been adequately investigated, despite the presence of several points in common. The finding of a connection between narcolepsy and autism spectrum disorder could boost the study of possible etiopathogenetic mechanisms shared between these two apparently so distant disorders. Basing on the literature data summarized in this paper, in the diagnostic work-up of a child with narcolepsy it is essential to evaluate also the social-communicative behavior using standardized tools in order to detect the real recurrence of clinical features suggesting an autism spectrum disorder. At the same time, it appears necessary to screen in the individuals with autism spectrum disorder for the possible presence of evoking symptoms of narcolepsy.

2020 - Can a Peer Support the Process of Self-Management in Narcolepsy? A Qualitative Narrative Analysis of a Narcoleptic Patient [Articolo su rivista]
Franceschini, C.; Fante, C.; Filardi, M.; Folli, M. C.; Brazzi, F.; Pizza, F.; D'Anselmo, A.; Ingravallo, F.; Antelmi, E.; Plazzi, G.

Introduction: Narcolepsy type 1 (NT1) is a chronic and rare sleep disorder typically arising during adolescence and young adulthood. The main symptoms are excessive daytime sleepiness and cataplexy, a prototypical fall down elicited by huge emotions. Social relationships, school, work, and general health perception are frequently impaired in patients, who often show lower quality-of-life scores. We report which management strategies a young patient (DMG) adopted to cope with NT1 during his growth, avoiding exhibiting serious impairments to his global functioning. Methods: A clinical psychologist explores the history of the patient’s disease and the self-acquired strategies used to cope with the symptoms. The patient’s global adaptation to the disease, stress-related managing skills, and overall well-being are assessed by standardized scales [Illness Behavior Questionnaire (IBQ); Coping Orientations to Problems Experienced (COPE); and Psychological General Well-Being Index (PGWBI)]. We conducted a qualitative analysis of the patient’s narration of his illness according to the procedure of the Grounded Theory. The MAXQDA software program was used to code the verbatim transcript. Results: From the qualitative analysis of the interview, three thematic cores emerged: 1) the disease history; 2) the patient’s friendship with AD, a friend of his age diagnosed with NT1 since childhood; 3) the strategies used to deal with his symptoms before the diagnosis of NT1 and the related treatment. From the psychometric tests, the patient presents good coping strategies in dealing with stressful problems and events based mainly on acceptance and positive reinterpretation of the stressful situation. Conclusion: This case shows that comparing peers of the same age and suffering from the same illness improve the patient’s self-management ability to cope and live well with NT1.

2020 - Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation [Articolo su rivista]
Postiglione, Emanuela; Antelmi, Elena; Pizza, Fabio; Stefano, Vandi; La Morgia, Chiara; Carelli, Valerio; Nassetti, Stefania; Seri, Marco; Plazzi, Giuseppe

Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.

2020 - Cerebrospinal fluid biomarkers of neurodegeneration in narcolepsy type 1 [Articolo su rivista]
Baiardi, Simone; Pizza, Fabio; Polischi, Barbara; Moresco, Monica; Abu-Rumeileh, Samir; Plazzi, Giuseppe; Parchi, Piero

To measure the levels of five neurodegenerative biomarkers in the cerebrospinal fluid (CSF) of patients with narcolepsy type 1 (NT1) with variable disease duration.

2020 - Childhood trauma, reflective functioning, and problematic mobile phone use among male and female adolescents [Articolo su rivista]
Musetti, A.; Brazzi, F.; Folli, M. C.; Plazzi, G.; Franceschini, C.

Background: The association between traumatic experiences, different forms of emotion dysregulation and problematic technology uses is well established. However, little is known about the role of childhood traumatic experiences and reflective functioning in the onset and maintenance of mobile phone addiction symptoms among adolescents. Methods: Self-reported measures on childhood traumatic experiences, reflective functioning, and Problematic Mobile Phone Use (PMPU) were administered to 466 high school students (47.1% females) aged 13-19 years old. Participants also reported the number of hours per day spent on using a mobile phone. Results: Hierarchical multiple regression analyses showed that increased time spent on the mobile phone, low reflective functioning scores and high childhood trauma scores predicted PMPU scores in the sample. Moreover, two gender-specific pathways were found. Among males, PMPU was positively related to time spent on mobile phone and childhood traumatic experiences and negatively related to reflective functioning. Among females, PMPU was negatively associated with time spent on mobile phone for video gaming and with reflective functioning. Conclusion: These results might have relevant clinical implications in highlighting the importance of planning gender-tailored interventions for adolescents who report mobile phone addiction symptoms.

2020 - Correction to: Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies (Acta Neuropathologica, (2020), 140, 1, (49-62), 10.1007/s00401-020-02160-8) [Articolo su rivista]
Rossi, M.; Candelise, N.; Baiardi, S.; Capellari, S.; Giannini, G.; Orru, C. D.; Antelmi, E.; Mammana, A.; Hughson, A. G.; Calandra-Buonaura, G.; Ladogana, A.; Plazzi, G.; Cortelli, P.; Caughey, B.; Parchi, P.

The article Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body.

2020 - Corrigendum to “Persistence of limb dystonia and myoclonus during sleep in corticobasal syndrome: a case series” (Sleep Medicine (2019) 59 (107–109), (S1389945718307093), (10.1016/j.sleep.2018.12.025)) [Articolo su rivista]
Infante, R.; Antelmi, E.; Pizza, F.; Maserati, M. S.; Plazzi, G.; Rizzo, G.; Liguori, R.

The authors regret that the original version of this article unfortunately contained a mistake in the affiliations for Elena Antelmi and Michelangelo Stanzani Maserati. This has now been corrected. The authors would like to apologise for any inconvenience caused.

2020 - Creativity in narcolepsy type 1: The role of dissociated rem sleep manifestations [Articolo su rivista]
D'Anselmo, A.; Agnoli, S.; Filardi, M.; Pizza, F.; Mastria, S.; Corazza, G. E.; Plazzi, G.

Purpose: A higher creative potential has been reported in narcoleptic patients and linked to lucid dreaming. The aim of the present study was to explore the role of narcolepsy symptoms (presence and severity) in predicting creativity. Patients and Methods: Sixty-six consecutive type 1 narcolepsy patients (mean age 38.62 ± 17.05, 31 females) took part in this study. Creative achievement in different life domains and creative beliefs were assessed by a self-reported questionnaire and a scale measuring the creative self, respectively; creative performance was measured through a divergent thinking test (generation of alternative original solutions to an open problem). Results: We found a key effect of hypnagogic hallucinations in modulating creative behaviour. We therefore tested at first whether hypnagogic hallucinations could interact with specific mental states associated with creativity and in particular mind wandering, a factor associated with both creative performance and achievement. Secondly, we verified if hypnagogic hallucinations could influence the definition of creative identity in type 1 narcolepsy patients, which in turn could predict their creative achievement and creative performance. Results showed that spontaneous mind wandering influenced creative achievement through a moderation effect of sleep paralysis and hypnagogic hallucinations. Moreover, sleep paralysis and hypnagogic hallucinations indirectly influenced, through creative identity, both creative achievement and performance (fluency score). Conclusion: Our results highlight the role of hypnagogic hallucinations in triggering the process of mind wandering which leads to greater creative success. In addition, this symptom affects creative identity in narcolepsy, leading in turn to higher creative success and creative potential of narcoleptic patients.

2020 - Defining Disrupted Nighttime Sleep and Assessing its Diagnostic Utility for Pediatric Narcolepsy Type 1 [Articolo su rivista]
Maski, Kiran; Pizza, Fabio; Liu, Shanshan; Steinhart, Erin; Little, Elaina; Colclasure, Alicia; Diniz Behn, Cecilia; Vandi, Stefano; Antelmi, Elena; Weller, Edie; Scammell, Thomas E; Plazzi, Giuseppe

Disrupted nighttime sleep (DNS) is a core narcolepsy symptom of unconsolidated sleep resulting from hypocretin neuron loss. In this study, we define a DNS objective measure and evaluate its diagnostic utility for pediatric narcolepsy type 1 (NT1).

2020 - Development and validation of volumetric absorptive microsampling coupled with UHPLC-MS/MS for the analysis of gamma-hydroxybutyric acid in human blood [Articolo su rivista]
Mohamed, Susan; Riva, Roberto; Moresco, Monica; Plazzi, Giuseppe; Contin, Manuela

A volumetric microsampling (VAMS) device (20 μl) was evaluated and validated for the analysis of γ-hydroxybutyric acid (GHB) in venous blood using a simple ultra-high-pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. GHB was extracted from VAMS device by acetonitrile, after a re-hydration step in a temperature-controlled ultrasonic bath at 60°C for 10 min. Chromatographic analysis was carried out on a Kinetex C18 column using 0.1% formic acid in water and acetonitrile as binary gradient mobile phase (from 5 to 95% of acetonitrile from 1 to 2.5 min) at a flow rate of 0.3 ml/min. The VAMS method was fully validated according to current guidelines with satisfactory results in terms of linearity, selectivity, precision, absolute recovery, matrix effect and stability. The linearity was determined from 0.5 to 200 μg/ml and the lower limit of quantitation was 0.5 μg/ml. The novel VAMS-UHPLC-MS/MS method was successfully compared with plasma-based method in a GHB-treated patient as a proof of concept.

2020 - Diagnosis of central disorders of hypersomnolence: A reappraisal by European experts [Articolo su rivista]
Lammers, G. J.; Bassetti, C. L. A.; Dolenc-Groselj, L.; Jennum, P. J.; Kallweit, U.; Khatami, R.; Lecendreux, M.; Manconi, M.; Mayer, G.; Partinen, M.; Plazzi, G.; Reading, P. J.; Santamaria, J.; Sonka, K.; Dauvilliers, Y.

The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence. The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes. We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context. We propose and define three diagnostic categories (with levels of certainty): 1/“Narcolepsy” 2/“Idiopathic hypersomnia”, 3/“Idiopathic excessive sleepiness” (with subtypes).

2020 - DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism [Articolo su rivista]
Maresca, Alessandra; Del Dotto, Valentina; Capristo, Mariantonietta; Scimonelli, Emanuela; Tagliavini, Francesca; Morandi, Luca; Tropeano, Concetta Valentina; Caporali, Leonardo; Mohamed, Susan; Roberti, Marina; Scandiffio, Letizia; Zaffagnini, Mirko; Rossi, Jacopo; Cappelletti, Martina; Musiani, Francesco; Contin, Manuela; Riva, Roberto; Liguori, Rocco; Pizza, Fabio; La Morgia, Chiara; Antelmi, Elena; Polosa, Paola Loguercio; Mignot, Emmanuel; Zanna, Claudia; Plazzi, Giuseppe; Carelli, Valerio

ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria but it is associated to the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as the result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.

2020 - Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder [Articolo su rivista]
Arnaldi, Dario; Chincarini, Andrea; Hu, Michele T; Sonka, Karel; Boeve, Bradley; Miyamoto, Tomoyuki; Puligheddu, Monica; De Cock, Valérie Cochen; Terzaghi, Michele; Plazzi, Giuseppe; Tachibana, Naoko; Morbelli, Silvia; Rolinski, Michal; Dusek, Petr; Lowe, Val; Miyamoto, Masayuki; Figorilli, Michela; de Verbizier, Delphine; Bossert, Irene; Antelmi, Elena; Meli, Riccardo; Barber, Thomas R; Trnka, Jiří; Miyagawa, Toji; Serra, Alessandra; Pizza, Fabio; Bauckneht, Matteo; Bradley, Kevin M; Zogala, David; McGowan, Daniel R; Jordan, Lennon; Manni, Raffaele; Nobili, Flavio

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.

2020 - Dream Generation and Recall in Daytime NREM Sleep of Patients With Narcolepsy Type 1 [Articolo su rivista]
Cipolli, C.; Pizza, F.; Bellucci, C.; Mazzetti, M.; Tuozzi, G.; Vandi, S.; Plazzi, G.

The less rigid architecture of sleep in patients with narcolepsy type 1 (NT1) compared with healthy subjects may provide new insights into some unresolved issues of dream experience (DE), under the assumption that their DE frequencies are comparable. The multiple transition from wakefulness to REM sleep (sleep onset REM period: SOREMP) during the five trials of the Multiple Sleep Latency Test (MSLT) appears of particular interest. In MSLT studies, NT1 patients reported a DE after about 80% of SOREMP naps (as often as after nighttime REM sleep of themselves and healthy subjects), but only after about 30% of NREM naps compared to 60% of daytime and nighttime NREM sleep of healthy subjects. To estimate accurately the “real” DE frequency, we asked participants to report DE (“dream”) after each MSLT nap and, in case of failure, to specify if they were unable to retrieve any content (“white dream”) or DE did not occur (“no-dream”). The proportions of dreams, white dreams, and no dreams and the indicators of structural organization of DEs reported after NREM naps by 17 adult NT1 patients were compared with those reported by 25 subjects with subjective complaints of excessive daytime sleepiness (sc-EDS), who take multiple daytime NREM naps. Findings were consistent with the hypothesis of a failure in recall after awakening rather than in generation during sleep: white dreams were more frequent in NT1 patients than in sc-EDS subjects (42.86 vs 17.64%), while their frequency of dreams plus white dreams were similar (67.86 and 61.78%) and comparable with that of NREM-DEs in healthy subjects. The longer and more complex NREM-DEs of NT1 patients compared with sc-EDS subjects suggest that the difficulty in DE reporting depends on their negative attitude toward recall of contents less vivid and bizarre than those they usually retrieve after daytime SOREMP and nighttime REM sleep. As this attitude may be reversed by some recall training before MSLT, collecting wider amounts of DE reports after NREM naps would cast light on both the across-stage continuity in the functioning of cognitive processes underlying DE and the difference in content and structural organization of SOREM-DEs preceded by N1 or also N2 sleep.

2020 - Evaluation and management of insomnia in clinical practice and in the time of CoViD-19 in Italy: Expert consensus and task-force recommendations from five scientific societies [Articolo su rivista]
Palagini, L.; Manni, R.; Aguglia, E.; Amore, M.; Brugnoli, R.; Girardi, P.; Grassi, L.; Mencacci, C.; Plazzi, G.; Minervino, A.; Nobili, L.; Biggio, G.

Insomnia symptoms might affect about 60% of the Italian population. Insomnia is a “24 hours syndrome” and a risk factor for medical and mental disorders. It should always be assessed and treated in the clinical practice. Cognitive Behavioral Therapy for Insomnia is the first line treatment but its availability in Italy is scarce. Pharmacological options in Italy are: melatonin 2 mg prolonged release that should be the first choice in subjects ≥55 years old and used until 13 weeks; and for a short term use (≤4 weeks) Z-drugs or short-acting benzodiazepines (in subjects <65 years old) or a sedating antidepressant.

2020 - Excessive daytime sleepiness in narcolepsy and central nervous system hypersomnias [Articolo su rivista]
Pizza, F.; Filardi, M.; Moresco, M.; Antelmi, E.; Vandi, S.; Neccia, G.; Mazzoni, A.; Plazzi, G.

Purpose: Excessive daytime sleepiness (EDS) is the core complaint of central nervous system (CNS) hypersomnias. In this mini-review, we summarized EDS features in CNS hypersomnias to provide a guide for differential diagnosis purposes. Methods: A review of recent literature was performed to provide an update in CNS hypersomnias. Results: At clinical evaluation, narcolepsy patients report a good restorative potential of sleep together with the frequent occurrence of dreaming even during short-lasting naps. These features are mirrored by the neurophysiological evidence of REM sleep at sleep onset (SOREMP) during the Multiple Sleep Latency Test (MSLT), a specific marker. Conversely, patients with idiopathic hypersomnia (IH) complain sleep inertia and prolonged nocturnal sleep. Polysomnographic studies show high sleep propensity on the MSLT or high 24-h total sleep time during continuous monitoring. Patients with insufficient sleep syndrome (ISS) can present with variable clinical EDS features in between narcolepsy and IH. ISS diagnosis is based on the clinical evidence of nocturnal sleep curtailment (weekdays versus vacations) associated with the disappearance of EDS complaint after sleep extension. Polysomnographic data are not required, but when the MSLT is performed, ISS patients can present with SOREMP arising from non-REM stage 2 sleep (vs narcolepsy patients entering into SOREM most frequently from wakefulness). Kleine-Levin Syndrome is characterized by recurrent episodes of enormously prolonged sleep time lasting days associated with abnormal cognition and behavior intermixed by asymptomatic periods, a sleep pattern that can be well documented by actigraphy. Conclusions: Different CNS hypersomnias present with specific features of EDS are useful to guide the clinician to apply and interpret appropriate neurophysiological investigations.

2020 - Expert Opinions and Consensus Recommendations for the Evaluation and Management of Insomnia in Clinical Practice: Joint Statements of Five Italian Scientific Societies [Articolo su rivista]
Palagini, Laura; Manni, Raffaele; Aguglia, Eugenio; Amore, Mario; Brugnoli, Roberto; Girardi, Paolo; Grassi, Luigi; Mencacci, Claudio; Plazzi, Giuseppe; Minervino, Antonino; Nobili, Lino; Biggio, Giovanni

Insomnia is the most commonly reported sleep problem in industrialized countries worldwide being present in about 36.8% of the general population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is most frequently observed as a comorbid condition and may precipitate, exacerbate, or prolong a broad range of comorbid conditions including physical and mental illnesses. Evaluating and targeting insomnia in the Italian clinical practice should be a priority.

2020 - Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies [Articolo su rivista]
Krohn, L.; Wu, R. Y. J.; Heilbron, K.; Ruskey, J. A.; Laurent, S. B.; Blauwendraat, C.; Alam, A.; Arnulf, I.; Hu, M. T. M.; Dauvilliers, Y.; Hogl, B.; Toft, M.; Bjornara, K. A.; Stefani, A.; Holzknecht, E.; Monaca, C. C.; Abril, B.; Plazzi, G.; Antelmi, E.; Ferini-Strambi, L.; Young, P.; Heidbreder, A.; Cochen De Cock, V.; Mollenhauer, B.; Sixel-Doring, F.; Trenkwalder, C.; Sonka, K.; Kemlink, D.; Figorilli, M.; Puligheddu, M.; Dijkstra, F.; Viaene, M.; Oertel, W.; Toffoli, M.; Gigli, G. L.; Valente, M.; Gagnon, J. -F.; Nalls, M. A.; Singleton, A. B.; Desautels, A.; Montplaisir, J. Y.; Cannon, P.; Ross, O. A.; Boeve, B. F.; Dupre, N.; Fon, E. A.; Postuma, R. B.; Pihlstrom, L.; Rouleau, G. A.; Gan-Or, Z.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results: A 5′-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020.

2020 - Flow cytometry T cell profiling in a recent-onset narcoleptic type 1 child: a case report [Articolo su rivista]
Moresco, M.; Lecciso, M.; Ocadlikova, D.; Pizza, F.; Curti, A.; Plazzi, G.

Background: Recent studies have disclosed the involvement of T cells in narcolepsy type 1 pathogenesis. We characterized the T cell subsets distribution in a recent-onset child at two different time points, two months from disease onset (T0) and 10 months later (follow-up), respectively. Methods: Peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) lymphocytes were characterized by flow cytometry at both evaluations. The distribution of T cell subsets was compared between the two time points, and the fold change was calculated as the CSF/PBMC frequencies ratio. Results: The patient showed a 2-fold increase in the frequency of CD4+ EMRA T cells, and an increase of more than one and a half in the frequency of CD4+ CM T cells in CSF at follow-up compared to T0. Moreover, the distribution of CD4+ EM T cells was slightly increased at T0 compared to follow-up. In PBMCs, the CD4+ and CD8+ T cell subsets showed a slight decrease in CM cells at the follow-up. Finally, the CSF/PBMC fold-change ratio showed a 3-fold increase of CD4+ and CD8+ CM T cells at the follow-up, a rise up to 1.5-fold of CD4+ EMRA subsets and a slight decrease in CD4+ EM T cells. Conclusions: Our data suggest that variations in the frequency of EM vs. CM of CD4+ and CD8+ T cell subsets in the CSF and in the CSF/PBMC fold change may represent a biological marker of disease progression.

2020 - GBA variants in REM sleep behavior disorder: a multicenter study [Articolo su rivista]
Krohn, Lynne; Ruskey, Jennifer A; Rudakou, Uladzislau; Leveille, Etienne; Asayesh, Farnaz; Hu, Michele T M; Arnulf, Isabelle; Dauvilliers, Yves; Högl, Birgit; Stefani, Ambra; Monaca, Christelle Charley; Beatriz, Abril; Plazzi, Giuseppe; Antelmi, Elena; Ferini-Strambi, Luigi; Heidbreder, Anna; Boeve, Bradley F; Espay, Alberto J; De Cock, Valérie Cochen; Mollenhauer, Brit; Sixel-Döring, Friederike; Trenkwalder, Claudia; Sonka, Karel; Kemlink, David; Figorilli, Michela; Puligheddu, Monica; Dijkstra, Femke; Viaene, Mineke; Oertel, Wolfgang; Toffoli, Marco; Gigli, Gian Luigi; Valente, Mariarosaria; Gagnon, Jean-François; Desautels, Alex; Montplaisir, Jacques Y; Postuma, Ronald B; Rouleau, Guy A; Gan-Or, Ziv

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.

2020 - Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies [Articolo su rivista]
Krohn, L.; Ozturk, T. N.; Vanderperre, B.; Ouled Amar Bencheikh, B.; Ruskey, J. A.; Laurent, S. B.; Spiegelman, D.; Postuma, R. B.; Arnulf, I.; Hu, M. T. M.; Dauvilliers, Y.; Hogl, B.; Stefani, A.; Monaca, C. C.; Plazzi, G.; Antelmi, E.; Ferini-Strambi, L.; Heidbreder, A.; Rudakou, U.; Cochen De Cock, V.; Young, P.; Wolf, P.; Oliva, P.; Zhang, X. K.; Greenbaum, L.; Liong, C.; Gagnon, J. -F.; Desautels, A.; Hassin-Baer, S.; Montplaisir, J. Y.; Dupre, N.; Rouleau, G. A.; Fon, E. A.; Trempe, J. -F.; Lamoureux, G.; Alcalay, R. N.; Gan-Or, Z.

Objective: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. Methods: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. Results: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. Interpretation: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139–153.

2020 - Giving a voice to cataplectic experience: Recollections from patients with narcolepsy type 1 [Articolo su rivista]
Franceschini, C.; Fante, C.; Folli, M. C.; Filosa, M.; Pizza, F.; Antelmi, E.; Ingravallo, F.; Plazzi, G.

Study Objectives: The objective of this study was to assess the narratives from the recalled accounts of cataplexy attacks of patients with narcolepsy type 1 (NT1). Methods: Twenty-two drug-naive adult patients meeting the International Classification of Sleep Disorders criteria for the diagnosis of NT1 referring to the Narcolepsy Center of the University of Bologna in the year 2017 underwent a semistructured interview focusing on their personal experiences during the cataplectic attacks. Verbatim transcripts were analyzed by thematic analysis of elementary contexts using T-LAB software. Results: The thematic analysis performed on the entire body text showed 3 clusters that explained 36.2%, 34.1%, and 29.7% of the variance, respectively: a cluster related to situations that trigger attacks of cataplexy, a cluster to bodily sensations, and another control strategies during episodes. The thematic content highlighted a tendency to disregard emotional experiences, thus affecting the ability to name, recognize, and regulate critical emotions. Conclusions: The study showed that patients with NT1 spoke of their cataplectic attacks in terms of self-reported bodily experiences, trigger situations, and their management. Therefore, patients may have developed strategies of symptom management focused on emotion avoidance and/or inhibition.

2020 - Immunotherapy in Narcolepsy [Articolo su rivista]
Giannoccaro, M. P.; Sallemi, G.; Liguori, R.; Plazzi, G.; Pizza, F.

Purpose of review: Narcolepsy type 1 (NT1) is a chronic and disabling sleep disorder due to the loss of hypocretinergic neurons in the lateral hypothalamus pathophysiologically linked to an autoimmune process. Current treatment is symptomatic, and no cure is available to date. Immunotherapy is considered a promising future therapeutic option, and this review discusses the rationale for immunotherapy in narcolepsy, current evidences of its effects, outcome measures, and future directions. Recent findings: A limited number of case reports and uncontrolled small case series have reported the effect of different immunotherapies in patients with NT1. These studies were mainly based on the use of intravenous immunoglobulin (IVig), followed by corticosteroids, plasmapheresis, and monoclonal antibodies. Although initial reports showed an improvement of symptoms, particularly when patients were treated close to disease onset, other observations have not confirmed these results. Inadequate timing of treatment, placebo effects, and spontaneous improvement due to the natural disease course can account for these contrasting findings. Moreover, clear endpoints and standardized outcome measures have not been used and are currently missing in the pediatric population. Summary: On the basis of the available data, there are no enough evidences to support the use of immunotherapy in NT1. Randomized, controlled studies using clear endpoints and new outcome measures are needed to achieve a definitive answer about the usefulness of these treatments in narcolepsy.

2020 - Impact of COVID-19 pandemic lockdown on narcolepsy type 1 management [Articolo su rivista]
Postiglione, E.; Pizza, F.; Ingravallo, F.; Vignatelli, L.; Filardi, M.; Mangiaruga, A.; Antelmi, E.; Moresco, M.; Oriolo, C.; Pagotto, U.; Plazzi, G.

Study Objectives: Narcolepsy type 1 (NT1) is a chronic rare hypersomnia of central origin requiring a combination of behavioral and pharmacological treatments. During the coronavirus disease 2019 (COVID-19) pandemic, in Italy the population was forced into a lockdown. With this study, we aimed to describe the lockdown impact on NT1 symptom management, according to different patients' working schedule. Methods: In the period between 10 April and 15 May 2020, we performed routine follow-up visits by telephone (as recommended during the COVID-19 emergency) to 50 patients >18 years old (40% males) under stable long-term treatment. We divided patients into three groups: unchanged working schedule, forced working/studying at home, and those who lost their job (“lost occupation”). Current sleep–wake habit and symptom severity were compared with prelockdown assessment (six months before) in the three patient groups. Results: At assessment, 20, 22, and eight patients belonged to the unchanged, working/studying at home, and lost occupation groups, respectively. While in the lost occupation group, there were no significant differences compared with prepandemic assessment, the patients with unchanged schedules reported more nocturnal awakenings, and NT1 patients working/studying at home showed an extension of nocturnal sleep time, more frequent daytime napping, improvement of daytime sleepiness, and a significant increase in their body mass index. Sleep-related paralysis/hallucinations, automatic behaviors, cataplexy, and disturbed nocturnal sleep did not differ. Conclusions: Narcolepsy type 1 patients working/studying at home intensified behavioral interventions (increased nocturnal sleep time and daytime napping) and ameliorated daytime sleepiness despite presenting with a slight, but significant, increase of weight.

2020 - Low CSF hypocretin-1 levels in an adult patient with hypothalamic hamartoma [Articolo su rivista]
Muccioli, L.; Bisulli, F.; Licchetta, L.; Pizza, F.; Moresco, M.; Martinoni, M.; Zucchelli, M.; Plazzi, G.; Tinuper, P.

2020 - Measures of functional outcomes, work productivity, and quality of life from a randomized, phase 3 study of solriamfetol in participants with narcolepsy [Articolo su rivista]
Emsellem, H. A.; Thorpy, M. J.; Lammers, G. J.; Shapiro, C. M.; Mayer, G.; Plazzi, G.; Chen, D.; Carter, L. P.; Villa, K. F.; Lee, L.; Menno, D.; Black, J.; Dauvilliers, Y.

Objective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy (75–150 mg/d) or obstructive sleep apnea (37.5–150 mg/d). In a randomized, double-blind, placebo-controlled trial in participants with narcolepsy, effects of solriamfetol on functional status, health-related quality of life (HRQoL), and work productivity were evaluated. Methods: Participants with narcolepsy (N = 239) were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), 36-Item Short Form Health Survey version 2 (SF-36v2), and Work Productivity and Activity Impairment questionnaire for Specific Health Problem (WPAI:SHP). A mixed-effects model with repeated measures was used for comparisons vs placebo. Results: At week 12, solriamfetol increased FOSQ-10 total score, with greatest mean difference from placebo (95% CI) at 300 mg (1.45 [0.31, 2.59]). On SF-36v2, improvements vs placebo were observed in physical component summary scores (300 mg: 2.22 [0.04, 4.41]) and subscales of role physical, general health, and vitality. On WPAI:SHP, solriamfetol 150 mg reduced overall work impairment vs placebo (−15.5 [−29.52, −1.47]), and 150 and 300 mg reduced activity impairment vs placebo (−10.05 [−19.48, −0.62] and −13.49 [−23.19, −3.78], respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Common TEAEs were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety. Conclusions: Solriamfetol improved measures of functional status, HRQoL, and work productivity, particularly at the 150- and 300-mg doses. Most TEAEs were mild to moderate. Trial registration: identifier NCT02348593, EudraCT number 2014-005487-15.

2020 - Meditation-Relaxation (MR Therapy) for Sleep Paralysis: A Pilot Study in Patients With Narcolepsy [Articolo su rivista]
Jalal, B.; Moruzzi, L.; Zangrandi, A.; Filardi, M.; Franceschini, C.; Pizza, F.; Plazzi, G.

Sleep paralysis (SP) is a condition where a person is paralyzed upon waking or falling asleep. SP afflicts ~20% of people, and is also one of the typical symptoms in narcolepsy. During SP the sleeper may experience hallucinations. Unsurprisingly, SP is associated with great fear globally. To date, there are no published clinical trials or outcome data for treating this condition. However, few non-pharmacological interventions have been proposed, including cognitive behavioral approaches, and case studies showing clinical amelioration with auto-hypnosis and Meditation-Relaxation (MR) therapy. The latter for instance showed positive preliminary results; when applied for 8 weeks it reduced SP frequency and anxiety/worry symptoms. With this paper we aimed to evaluate, with a small-scale pilot study, the efficacy of MR therapy for SP in patients with narcolepsy. Ten patients with narcolepsy and SP were enrolled in the study. Notably, MR therapy (n = 6), applied for 8 weeks, resulted in a dramatic decrease in the number of days SP occurred (50% reduction); and the total number of SP episodes (54% reduction) in the last month of the study (demonstrated by large within-group effect sizes); unlike the control intervention (deep breathing) (n = 4). These findings are preliminary and exploratory given the small sample. Nonetheless, they represent the first proof of concept at providing empirically-guided insights into the possible efficacy of a novel treatment for frequently occurring SP. Although the study was conducted in patients with narcolepsy we cautiously suggest that the findings may generalize to individuals with isolated SP.

2020 - Narcolepsy is a paediatric disease: Use red flags to recognise it [Articolo su rivista]
Antelmi, E.; Vignatelli, L.; Ceretelli, I.; Bellini, M.; Carta, C.; Cortelli, P.; Guerrini, R.; Ingravallo, F.; Marchiani, V.; Mari, F.; Pieroni, G.; Pizza, F.; Verga, C.; Verillo, E.; Strambi, L. F.; Ferri, R.; Taruscio, D.; Plazzi, G.

Rationale - Narcolepsy is a chronic rare disease that frequently develops in children. It is characterised by excessive daily sleepiness, cataplexy, sleep paralysis, hypnagogic and hypnopompic hallucinations as well as disturbed nocturnal sleep. Moreover, psychiatric disorders, obesity and early puberty can complete the clinical picture. Narcolepsy diagnosis is often delayed and many patients receive wrong diagnoses and inappropriate treatments. Objective - The Associazione Italiana Narcolettici e Ipersonni (AIN) promoted the “Red Flags Project” in order to increase early detection by doctors that visit subjects with narcolepsy symptoms. The project has been developed by a multidisciplinary panel including main Scientific Societies involved in narcolepsy diagnosis, with the methodological contribution of the Neurological Sciences Institute of Bologna University and Istituto Superiore di Sanità. Method - The project has been divided into three phases. Phase 1: preparation of a questionnaire aimed at defining diagnostic delay, barriers and solutions and questionnaire filling in by Scientific Societies representatives and AIN members. Phase 2: shaping of typical and atypical narcolepsy pictures in adults and in children, on whose basis Red Flags have been defined. Phase 3: the panel has produced suggestions aimed at Red Flags spreading and barriers overcoming. Results - Narcolepsy Red Flags are 5 paradigmatic clinical pictures: 3 for children and 2 for adults. The limited early symptoms knowledge of doctors, in particular on symptoms different from sleep attacks, is the main barrier to diagnosis. Conclusions - “Red Flags Project” deals with diagnostic delay, proposing paradigmatic clinical pictures, in order to arouse diagnostic suspect and suggest targets of Red Flags spreading.

2020 - Narcolepsy treatment: pharmacological and behavioral strategies in adults and children [Articolo su rivista]
Franceschini, Christian; Pizza, Fabio; Antelmi, Elena; Folli, Maria Claudia; Plazzi, Giuseppe

Narcolepsy is a disabling, rare, and chronic sleep disorder, currently classified as distinct central nervous system hypersomnia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Although today a reliable pathogenic hypothesis identifies the cause of NT1 as an autoimmune process destroying hypocretin-producing cells, there is no cure for narcolepsy, and the symptomatic pharmacological available treatments are not entirely effective for all symptoms. Behavioral therapies play a synergistic role in the disease treatment. We here review the available therapeutic options for narcolepsy, including symptomatic pharmacological treatments as well as behavioral and psychosocial interventions that could help clinicians improve the quality of life of patients with narcolepsy in adulthood and childhood.

2020 - (Not so) Smart sleep tracking through the phone: Findings from a polysomnography study testing the reliability of four sleep applications [Articolo su rivista]
Fino, E.; Plazzi, G.; Filardi, M.; Marzocchi, M.; Pizza, F.; Vandi, S.; Mazzetti, M.

An increasing number of sleep applications are currently available and are being widely used for in-home sleep tracking. The present study assessed four smartphone applications (Sleep Cycle-Accelerometer, SCa; Sleep Cycle-Microphone, SCm; Sense, Se; Smart Alarm, SA) designed for sleep−wake detection through sound and movement sensors, by comparing their performance with polysomnography. Twenty-one healthy participants (six males, 15 females) used the four sleep applications running on iPhone (provided by the experimenter) simultaneously with portable polysomnography recording at home, while sleeping alone for two consecutive nights. Whereas all apps showed a significant correlation with polysomnography-time in bed, only SA offered significant correlations for sleep efficacy. Furthermore, SA seemed to be quite effective in reliable detection of total sleep time and also light sleep; however, it underestimated wake and partially overestimated deep sleep. None of the apps resulted capable of detecting and scoring rapid eye movement sleep. To sum up, SC (functioning through both accelerometer and microphone) and Se did not result sufficiently reliable in sleep−wake detection compared with polysomnography. SA, the only application offering the possibility of an epoch-by-epoch analysis, showed higher accuracy than the other apps in comparison with polysomnography, but it still shows some limitations, particularly regarding wake and deep sleep detection. Developing scoring algorithms specific for smartphone sleep detection and adding external sensors to record other physiological parameters may overcome the present limits of sleep tracking through smart phone apps.

2020 - Objective rest–activity cycle analysis by actigraphy identifies isolated rapid eye movement sleep behavior disorder [Articolo su rivista]
Filardi, M.; Stefani, A.; Holzknecht, E.; Pizza, F.; Plazzi, G.; Hogl, B.

Background and purpose: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest–activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls. Methods: Nineteen patients with video-polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep [19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS)] and 16 healthy controls underwent 2-week actigraphy and video-polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non-parametric analyses were applied to assess the rest–activity rhythm features. Results: Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I < O, a 24-h measure that expresses the relationship between nocturnal and diurnal motor activity intensity, distinguished patients with iRBD from those with RLS, those with SAS and controls, with an area under the curve greater than that of REM sleep behavior disorder screening questionnaires. An I < O of 98.32 shows the best balance between sensitivity (63.2%) and specificity (89.1%). Discussion: The I < O index distinguished iRBD patients from those with other pathological motor activity during sleep and controls, confirming its use as an objective measure suitable to screen large at-risk populations.

2020 - Pharmacokinetics of pitolisant in children and adolescents with narcolepsy [Articolo su rivista]
Lecendreux, M.; Plazzi, G.; Franco, P.; Jacqz-Aigrain, E.; Robert, P.; Duvauchelle, T.; Schwartz, J. -C.

Objective: To evaluate the pharmacokinetic profile and tolerability of pitolisant, a selective histamine 3 (H3)−receptor antagonist/inverse agonist, in children and adolescents with narcolepsy. Methods: This multicenter, open-label, single-dose study of pitolisant 17.8 mg enrolled patients aged 6 through 17 years with a diagnosis of narcolepsy. Blood samples were collected at prespecified time points for analysis of pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the serum concentration–time curve from time 0–10 h (AUC0–10h). Pharmacokinetic parameters were compared across three prespecified age groups: younger pediatric patients (aged 6 to <12 years), older pediatric patients (aged 12 to <18 years), and a historical comparison group of young adults (aged 18 to <45 years). Results: Of the 25 enrolled patients, 24 were included in the pharmacokinetic analysis. Pitolisant Cmax and AUC0–10h were greater (by 52% and 73%, respectively) in the younger (n = 12) versus older (n = 12) pediatric subgroup. These parameters were lower in the young adult group (n = 13) by 51% and 48%, respectively, compared with the older pediatric patients, and by 68% and 70%, respectively, compared with the younger pediatric patients. There were six treatment-emergent adverse events: headache (three), dizziness (one), diarrhea (one), and vomiting (one). Conclusions: After single-dose administration, the exposure parameters of pitolisant were significantly greater in the younger compared with older pediatric patients with narcolepsy. Pitolisant doses up to 17.8 mg/d (in children with body weight <40 kg) or 35.6 mg/d are appropriate for further evaluation in pediatric patients. Trial registration: EudraCT Number: 2013-001505-93.

2020 - Poor sleep quality and its consequences on mental health during the COVID-19 lockdown in Italy [Articolo su rivista]
Franceschini, C.; Musetti, A.; Zenesini, C.; Palagini, L.; Scarpelli, S.; Quattropani, M. C.; Lenzo, V.; Freda, M. F.; Lemmo, D.; Vegni, E.; Borghi, L.; Saita, E.; Cattivelli, R.; De Gennaro, L.; Plazzi, G.; Riemann, D.; Castelnuovo, G.

Background: Coronavirus disease 2019 (COVID-19) seriously affected the whole of Italy. The extreme virulence and the speed of propagation resulted in restrictions and home confinement. This change was immediately perceived by people who found themselves exposed to feelings of uncertainty, fear, anger, stress, and a drastic change in the diurnal but above all nocturnal lifestyle. For these reasons, we aimed to study the quality of sleep and its connection to distress levels and to evaluate how lifestyle changed in the Italian population during the lockdown. Methods: By means of an Internet survey we recruited 6,519 adults during the whole of the COVID-19 lockdown (from March 10–1st phase to May 4–2nd phase). We investigated the sociodemographic and COVID-19-related information and assessed sleep quality using the Medical Outcomes Study–sleep scale (MOS-SS) and mental health with the short form of Depression, Anxiety, and Stress Scales–21 Items (DASS-21). Multiple logistic regression model was used to evaluate the multivariate association between the dependent variable (good sleeper vs. poor sleeper) and all the variables that were significant in the univariate analysis. Results: A total of 3,562 (55.32%) participants reported poor sleep quality according to the MOS-Sleep Index II score. The multiple binary logistic regression results of poor sleepers revealed several risk factors during the outbreak restrictions: female gender, living in Central Italy, having someone close who died because of COVID-19, markedly changed sleep–wake rhythms characterized by earlier or postponed habitual bedtime, earlier habitual awakening time and reduced number of afternoon naps, and extremely severe levels of stress, anxiety, and depression. Conclusion: This is the first study designed to understand sleep quality and sleep habits during the whole of the lockdown period in the Italian population that provides more than 6,000 participants in a survey developed specifically for the health emergency related to COVID-19. Our study found that more than half of the Italian population had impaired sleep quality and sleep habits due to elevated psychological distress during the COVID-19 lockdown containment measures. A multidisciplinary action should be undertaken in order to plan appropriate responses to the current crisis caused by the lockdown for the COVID-19 outbreak.

2020 - Population and Noncompartmental Pharmacokinetics of Sodium Oxybate Support Weight-Based Dosing in Children and Adolescents With Narcolepsy With Cataplexy [Articolo su rivista]
Chen, C.; Rosen, C. L.; Ruoff, C.; Boyce, L. H.; Parvataneni, R.; Zomorodi, K.; Brantley, S.; Sale, M.; Plazzi, G.

The pharmacokinetics (PKs) of sodium oxybate (SXB) was evaluated in a subset of participants from a study of SXB treatment in children (aged 7–11 years; n = 11) and adolescents (aged 12–17 years; n = 18) with narcolepsy with cataplexy. PK evaluation was conducted over 2 nights during the period when participants received a stable nightly SXB dose. The SXB dose on night 1 was half of night 2 and was administered in two equally divided doses: dose 1 was administered > 2 hours after the evening meal, and dose 2 was administered ≥ 4 hours after dose 1. Noncompartmental PK analysis demonstrated higher plasma concentrations post-dose 2 vs. post-dose 1, higher than dose-proportional increases in area under the concentration-time curve from 0 to 4 hours (AUC0–4h) after dose 1, indicating nonlinear clearance, and better correlation between exposure and mg/kg than exposure and gram dose. To confirm the noncompartmental findings, identify factors affecting SXB PK, and compare with prior results in adults, a population PK (PopPK) model was established combining PK data from the current study with prior data from adults (132 healthy volunteers and 13 with narcolepsy). A two-compartment PopPK model with first-order absorption and nonlinear clearance from the central compartment described the data well. PopPK identified weight as the main intrinsic factor and food as the main extrinsic factor affecting SXB PK, and predicts similar PK profiles on a mg/kg basis across ages. These results, along with previously reported efficacy and safety outcomes, support weight-based SXB dose initiation in pediatric patients.

2020 - Pre-race sleep management strategy and chronotype of offshore solo sailors [Articolo su rivista]
Filardi, M.; Morini, S.; Plazzi, G.

Purpose: To evaluate chronotype and the sleep management strategy adopted by sailors before the offshore solo sailing race “Mini Transat La Boulangère”. As secondary aim, we assessed whether adopting pre-race sleep management strategy influences performance at race. Materials and Methods: Forty-two solo sailors completed questionnaires on sleep quality, sleepiness, chronotype and an ad hoc questionnaire on the pre-race sleep management strategy adopted. Arrival times, separately for each race’s leg, were provided by the race organization team. Results: Solo sailors present mainly with a morning-type (40%) and intermediate-type (60%) chronotype, while none have an evening-type chronotype. Fifty-five percent of sailors adopted pre-race sleep management strategy. Sailors that adopted strategy have travelled more miles in offshore compared to sailors that did not adopt strategy (p<0.05). Significant differences emerged in rMEQ scores, with sailors that adopted strategy presenting lower score compared to sailors that did not adopt sleep strategy (p<0.05), as well as in chronotype distribution with morning-type sailors that are less likely to adopt pre-race sleep management strategy compared to intermediate type sailors (p<0.05). No differences emerged in final arrival times and in arrival time at leg1 and leg2. The most commonly adopted strategy (52% of sailors) consists of sleep extension, followed by the polyphasic sleep (26%), and sleep deprivation (22%) strategy. Sailors trained in polyphasic sleep have higher ESS than sailors trained in sleep deprivation (p<0.05). Conclusion: Morning-type chronotype is overrepresented in this large cohort of solo sailors compared to the general population; moreover, chronotype seems to influence the adoption of sleep management strategy. A little over half of solo sailors participating in the Mini Transat trained in sleep management strategy before the race; however, neither the general adoption of pre-race sleep management strategy nor the adoption of a specific sleep strategy seems to significantly influence final arrival times.

2020 - Prevalence and neurophysiological correlates of sleep disordered breathing in pediatric type 1 narcolepsy [Articolo su rivista]
Filardi, M.; Demir, N.; Pizza, F.; Vandi, S.; Antelmi, E.; Noce, S.; Bruni, O.; Plazzi, G.

Study objectives: To investigate the prevalence and neurophysiological correlates of obstructive sleep disordered breathing (OSA) in type 1 narcolepsy (NT1) children and adolescents. Methods: Thirty-eight, drug-naïve, NT1 children and adolescents and 21 age- and sex-balanced clinical controls underwent nocturnal polysomnography (PSG) and multiple sleep latency test (MSLT). According to the rules for pediatric population, an obstructive apnea-hypopnea index (Obstructive AHI) ≥ 1 (comprising obstructive and mixed events), defined comorbid OSA. Results: NT1 children showed higher prevalence of overweight/obesity and severe nocturnal sleep disruption (lower sleep efficiency, and increased N1 sleep stage percentage) coupled with higher motor activity (periodic limb movement index [PLMi] and REM atonia index) compared to clinical controls. Sleep-related respiratory variables did not differ between NT1 and clinical controls (OSA prevalence of 13.2% and 4.8%, respectively). NT1 children with OSA were younger and showed lower N2 sleep stage percentage and higher PLMi than NT1 children without comorbid OSA. Overweight/obesity was not associated with OSA in NT1. Conclusions: Despite higher body mass index (BMI), OSA prevalence did not differ between children with NT1 and clinical controls. OSA in pediatric NT1 patients is a rare and mild comorbidity, further contributing to nocturnal sleep disruption without effects on daytime sleepiness.

2020 - Protocols of a diagnostic study and a randomized controlled non-inferiority trial comparing televisits vs standard in-person outpatient visits for narcolepsy diagnosis and care: TElemedicine for NARcolepsy (TENAR) [Articolo su rivista]
Ingravallo, F.; Vignatelli, L.; Pagotto, U.; Vandi, S.; Moresco, M.; Mangiaruga, A.; Oriolo, C.; Zenesini, C.; Pizza, F.; Plazzi, G.

Background: Narcolepsy is a rare chronic sleep disorder that typically begins in youth. Excessive daytime sleepiness is the main disabling symptom, but the disease is often associated with severe endocrine-metabolic and psychosocial issues, worsened by a long diagnostic delay, requiring a multidisciplinary approach. The scarcity of reference Sleep Centres forces the patient and family to travel for seeking medical consultations, increasing the economic and psychosocial burden of the disease. Growing evidence suggests that Telemedicine may facilitate patient access to sleep consultations and its non-inferiority in terms of patient satisfaction, adherence to treatment, and symptom improvement for sleep disorders. However, Telemedicine clinical and economic benefits for patients with narcolepsy are still unknown. Methods: TENAR is a two-part project, including: 1. a cross-sectional study (involving 250 children and adults with suspected narcolepsy) evaluating the accuracy of Teletriage (i.e., a synchronous live interactive sleep assessment through a Televisit) for narcolepsy diagnosis compared to the reference standard; and 2. a two-arm, parallel, open randomized controlled trial (RCT) to demonstrate the non-inferiority of the multidisciplinary care of narcolepsy through Televisits versus standard care. In this RCT, 202 adolescents (> 14 y.o.) and adults with narcolepsy will be randomly allocated (1:1 ratio) either to Televisits via videoconference or to standard in-person outpatient follow-up visits (control arm). The primary outcome is sleepiness control (according to the Epworth Sleepiness Scale). Secondary outcomes are other symptoms control, compliance with treatment, metabolic control, quality of life, feasibility, patient and family satisfaction with care, safety, and disease-related costs. At baseline and at 12 months, patients will undergo neurologic, metabolic, and psychosocial assessments and we will measure primary and secondary outcomes. Primary outcomes will be also measured at 6 months (remotely or in person, according to the arm). Discussion: TENAR project will assess, for the first time, the feasibility, accuracy, efficacy and safety of Telemedicine procedures applied to the diagnosis and the multidisciplinary care of children and adults with narcolepsy. The study may be a model for the remote management of other rare disorders, offering care access for patients living in areas lacking medical centres with specific expertise. Trial registration: Number of the Tele-multidisciplinary care study NCT04316286. Registered 20 March 2020.

2020 - Rapid eye movement sleep behavior disorder and sodium oxybate: Efficacy and viewpoint [Articolo su rivista]
Antelmi, E.; Plazzi, G.

2020 - REM sleep behavior disorder in narcolepsy: A secondary form or an intrinsic feature? [Articolo su rivista]
Antelmi, E.; Pizza, F.; Franceschini, C.; Ferri, R.; Plazzi, G.

Disrupted nighttime sleep is one of the pentad of symptoms defining Narcolepsy. REM sleep behavior disorder (RBD) largely contributes to night sleep disruption and narcolepsy is the most common cause of secondary RBD. However, RBD linked to narcolepsy (N-RBD) has been insufficiently characterized, leaving unsolved a number of issues. Indeed, it is still debated whether N-RBD is an intrinsic feature of narcolepsy, as indubitable for cataplexy, and therefore strictly linked to the cerebrospinal fluid hypocretin-1 (CSF hcrt-1) deficiency, or an associated feature, with a still unclear pathophysiology. The current review aims at rendering a comprehensive state–of-the-art of N-RBD, highlighting the open and unsettled topics. RBD reportedly affects 30–60% of patients with Narcolepsy type 1 (NT1), but it may be seen also in Narcolepsy type 2 (NT2). When compared to idiopathic/isolated RBD (iRBD), N-RBD has been reported to be characterized by less energetic and quieter episode, which however occur with the same probability in the first and the second part of the night and sometime even subcontinuously. N-RBD patients are generally younger than those with iRBD. N-RBD has been putatively linked to wake-sleep instability due to CSF hcrt-1 deficiency, but this latter by itself cannot explain completely the phenomenon as N-RBD has not been universally linked to low CSF hcrt-1 levels and it may be observed also in NT2. Therefore, other factors may probably play a role and further studies are needed to clarify this issue. In addition, therapeutic options have been poorly investigated.

2020 - Resilience Contributes to Low Emotional Impact of the COVID-19 Outbreak Among the General Population in Italy [Articolo su rivista]
Lenzo, V.; Quattropani, M. C.; Musetti, A.; Zenesini, C.; Freda, M. F.; Lemmo, D.; Vegni, E.; Borghi, L.; Plazzi, G.; Castelnuovo, G.; Cattivelli, R.; Saita, E.; Franceschini, C.

Background: The COVID-19 outbreak is severely affecting the overall mental health with unknown psychological consequences. Although a strong psychological impact is possible, scant evidence is available to date. Past studies have shown that resilience decreases the negative effects of stress. This study aimed to examine depression, anxiety, and stress among the Italian general population during the phase characterized by lockdown, and to investigate the role of resilience as a potential predictor. Methods: A total sample of 6,314 Italian people participated in this study. Participants were recruited between March 29 and May 04 2020 through an online survey. The Depression Anxiety Stress Scales-21 (DASS-21) and the Resilience Scale (RS) were administered. Demographic data and lockdown related information were also collected. A correlational analysis was carried out to examine relationships between psychopathological domains and resilience. Three hierarchical regression analyses were conducted using the depression, anxiety, and stress as dependent variables and the resilience as independent variable controlling for age, gender, and education. COVID-19 specific variables were also included in the three regression analyses. A further exploratory analysis was carried out to examine which aspects of resilience predict depression, anxiety, and stress. Results: The prevalence of moderate to extremely severe symptoms among participants was 32% for depression, 24.4% for anxiety, and 31.7% for stress. The sample mean scores on depression, anxiety, and stress were higher than the normal scores reported in the literature. Results of correlational analysis showed that resilience factors, such as meaningfulness, self-reliance, existential aloneness, and equanimity, are inversely associated with depression, anxiety, and stress. Results of regression analyses indicated that resilience was statically significant in predicting depression, anxiety, and stress. Geographic area of residence and infected acquaintances were also significant predictors. Regarding the resilience factors, results revealed that meaningfulness, perseverance, and equanimity were statistically significant in predicting all the DASS-21 scales. Conclusion: About a third of respondents reported moderate to extremely severe depression, anxiety, and stress. The present study suggests that psychological resilience may independently contribute to low emotional distress and psychological ill-being. These findings can help explain the variability of individual responses during the COVID-19 outbreak.

2020 - Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients [Articolo su rivista]
Licchetta, L.; Pippucci, T.; Baldassari, S.; Minardi, R.; Provini, F.; Mostacci, B.; Plazzi, G.; Tinuper, P.; Bisulli, F.; Bianchi, A.; Striano, P.; Gambardella, A.; Giordano, L.; Santucci, M.; Meletti, S.; Crichiutti, G.; Marini, C.; Vignoli, A.; Dilena, R.; Briatore, E.

Purpose: Genetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome. Methods: We selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results: We included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD). We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD. Conclusions: The overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.

2020 - SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder [Articolo su rivista]
Rudakou, U.; Futhey, N. C.; Krohn, L.; Ruskey, J. A.; Heilbron, K.; Cannon, P.; Alam, A.; Arnulf, I.; Hu, M. T. M.; Montplaisir, J. Y.; Gagnon, J. -F.; Desautels, A.; Dauvilliers, Y.; Toffoli, M.; Gigli, G. L.; Valente, M.; Hogl, B.; Stefani, A.; Holzknecht, E.; Sonka, K.; Kemlink, D.; Oertel, W.; Janzen, A.; Plazzi, G.; Antelmi, E.; Figorilli, M.; Puligheddu, M.; Mollenhauer, B.; Trenkwalder, C.; Sixel-Doring, F.; De Cock, V. C.; Monaca, C. C.; Heidbreder, A.; Ferini-Strambi, L.; Dijkstra, F.; Viaene, M.; Abril, B.; Boeve, B. F.; Postuma, R. B.; Rouleau, G. A.; Gan-Or, Z.

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.

2020 - Solriamfetol for the Treatment of Excessive Daytime Sleepiness in Participants with Narcolepsy with and without Cataplexy: Subgroup Analysis of Efficacy and Safety Data by Cataplexy Status in a Randomized Controlled Trial [Articolo su rivista]
Dauvilliers, Y.; Shapiro, C.; Mayer, G.; Lammers, G. J.; Emsellem, H.; Plazzi, G.; Chen, D.; Carter, L. P.; Lee, L.; Black, J.; Thorpy, M. J.

Background: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy. Objective: Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status. Methods: Participants with narcolepsy received solriamfetol (75, 150, or 300 mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; therefore p values are nominal. Results: There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were 1.6 (− 3.6 to 6.9), 6.1 (0.7–11.4), and 8.9 (3.5–14.2) minutes, respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup were 3.4 (− 1.9 to 8.7), 9.1 (3.8–14.3), and 11.2 (5.8–16.6) minutes, respectively (p < 0.001; 150 and 300 mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were − 1.3 (− 3.9 to 1.3), − 3.7 (− 6.4 to − 1.1), and − 4.5 (− 7.1 to − 1.9), respectively (p < 0.01; 150 and 300 mg), and in the non-cataplexy subgroup were − 3.0 (− 5.6 to − 0.4), − 3.7 (− 6.3 to − 1.2), and − 4.9 (− 7.6 to − 2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup was 10% (− 15 to 35), 33% (9–57), and 39% (16–61), respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup was 48% (25–70), 44% (21–67), and 52% (30–73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75 mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean ± standard deviation changes: − 3.6 ± 13.3 [combined solriamfetol] and − 3.5 ± 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups. Conclusions: These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status. Trial Registration and Date: NCT02348593. 28 January 2015.

2020 - Solriamfétol (JZP-110) pour le traitement de la somnolence diurne excessive (SDE) chez les patients avec narcolepsie avec et sans cataplexie : résultats d’un essai clinique de phase 3 randomisé [Articolo su rivista]
Dauvilliers, Y.; Shapiro, C.; Mayer, G.; Lammers, G. J.; Emsellem, H.; Plazzi, G.; Chen, D.; Carter, L. P.; Lee, L.; Thorpy, M. J.

2020 - Structural Organization of Dream Experience During Daytime Soremp Sleep of Patients with Narcolepsy Type 1 [Articolo su rivista]
Cipolli, Carlo; Pizza, Fabio; Bellucci, Claudia; Mazzetti, Michela; Tuozzi, Giovanni; Vandi, Stefano; Plazzi, Giuseppe

To assess the frequency of dream experience (DE) developed during naps at Multiple Sleep Latency Test (MSLT) by patients with narcolepsy type-1 (NT1) and establish, using story-grammar analysis, the structural organization of DEs developed during naps with sleep onset REM period (SOREMP) sleep compared with their DEs during early-and late-night REM sleep.

2020 - Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies [Articolo su rivista]
Rossi, M.; Candelise, N.; Baiardi, S.; Capellari, S.; Giannini, G.; Orru, C. D.; Antelmi, E.; Mammana, A.; Hughson, A. G.; Calandra-Buonaura, G.; Ladogana, A.; Plazzi, G.; Cortelli, P.; Caughey, B.; Parchi, P.

The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein.

2019 - A randomized study of solriamfetol for excessive sleepiness in narcolepsy [Articolo su rivista]
Thorpy, M. J.; Shapiro, C.; Mayer, G.; Corser, B. C.; Emsellem, H.; Plazzi, G.; Chen, D.; Carter, L. P.; Wang, H.; Lu, Y.; Black, J.; Dauvilliers, Y.

Objective: Solriamfetol (JZP-110) is a selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects. This phase 3 study (NCT02348593) evaluated the safety and efficacy of solriamfetol in narcolepsy. Methods: Patients with narcolepsy with mean sleep latency <25 minutes on the Maintenance of Wakefulness Test (MWT), Epworth Sleepiness Scale (ESS) score ≥10, and usual nightly sleep ≥6 hours were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Coprimary endpoints were change from baseline to week 12 in MWT and ESS. Improvement on the Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Results: Safety and modified intention-to-treat populations included 236 and 231 patients, respectively. Solriamfetol 300 and 150 mg were positive on both coprimary endpoints. Least squares mean (standard error [SE]) changes from baseline were 12.3 (SE = 1.4) and 9.8 (SE = 1.3) minutes for solriamfetol 300 and 150 mg on the MWT, respectively, versus 2.1 (SE = 1.3) minutes for placebo, and −6.4 (SE = 0.7) for 300 mg and −5.4 (SE = 0.7) for 150 mg on the ESS versus −1.6 (SE = 0.7) for placebo (all p < 0.0001). At week 12, higher percentages of patients treated with solriamfetol 150 mg (78.2%) and 300 mg (84.7%) reported PGI-C improvement relative to placebo (39.7%; both p < 0.0001). Adverse events ≥5% across all solriamfetol doses included headache (21.5%), nausea (10.7%), decreased appetite (10.7%), nasopharyngitis (9.0%), dry mouth (7.3%), and anxiety (5.1%). Interpretation: Solriamfetol has the potential to be an important therapeutic option for the treatment of impaired wakefulness and excessive sleepiness in patients with narcolepsy. ANN NEUROL 2019;85:359–370.

2019 - A standardized test to document cataplexy [Articolo su rivista]
Vandi, Stefano; Pizza, Fabio; Antelmi, Elena; Neccia, Giulia; Iloti, Martina; Mazzoni, Alice; Avoni, Patrizia; Plazzi, Giuseppe

Objective/Background: Cataplexy is the pathognomonic symptom of narcolepsy type 1 (NT1). Since it is considered difficult to be directly observed or documented by clinicians, its diagnosis relies mainly on history taking. Our study aimed at testing the feasibility of a standardized video recording procedure under emotional stimulation to document cataplexy in the diagnostic work-up of suspected hypersomnia of central origin. Patients/Methods: Two-hundred-eight consecutive patients underwent the diagnostic work-up and reached the final diagnosis of NT1 (n = 133), idiopathic hypersomnia or narcolepsy type 2 (IH/NT2 group, n = 33), or subjective excessive daytime sleepiness (sEDS group, n = 42). All subjects underwent a standardized video recording procedure while watching funny movies selected according to individual preferences, and a technician blind to clinical features reviewed the recordings to identify hypotonic phenomena that were finally confirmed by patients. Results: The video recording under emotional stimulation captured hypotonic phenomena in 72.2%, 9.1% and 4.8% of NT1, IH/NT2, and sEDS subjects (p < 0.0001), respectively. When tested against CSF hypocretin deficiency, the documentation of a hypotonic episode at the test showed an area under the ROC curve of 0.823 ± 0.033 (p < 0.0001). NT1 patients under anticataplectic medications showed less frequently hypotonic episodes than untreated ones (48.0% vs 77.8%, p = 0.003). Conclusions: A standardized video recording procedure under emotional stimulation can help in the characterization of suspected hypersomnia of central origin. Further multi-center studies are warranted to extend the present findings and integrate a shared procedure for the laboratory work-up of narcolepsy.

2019 - Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility [Articolo su rivista]
Donadio, V; Doppler, K; Incensi, A; Kuzkina, A; Janzen, A; Mayer, G; Volkmann, J; Rizzo, G; Antelmi, E; Plazzi, G; Sommer, C; Liguori, R; Oertel, W H

Visualization of phosphorylated α-synuclein at serine 129 (p-syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here we aimed to establish the intra- and inter-laboratory reproducibility of quantification of intraneural p-syn immunoreactivity in two laboratories with a major expertise (Würzburg and Bologna).

2019 - Biomarkers for REM sleep behavior disorder in idiopathic and narcoleptic patients [Articolo su rivista]
Antelmi, Elena; Pizza, Fabio; Donadio, Vincenzo; Filardi, Marco; Sosero, YURI LUDWIG; Incensi, Alex; Vandi, Stefano; Moresco, Monica; Ferri, Raffaele; Marelli, Sara; Ferini-Strambi, Luigi; Liguori, Rocco; Plazzi, Giuseppe

To search for discriminating biomarkers, 30 patients with idiopathic rapid-eye-movements sleep behavior disorder (iRBD) were compared with 17 patients with RBD within narcolepsy type 1. Both groups underwent extensive examinations, including skin biopsy searching for phosphorylated alpha-synuclein deposits and whole-night video-polysomnography. Skin biopsy was positive for phosphorylated alpha-synuclein deposits in 86.7% of iRBD patients and in none of narcoleptic patients. The analysis of video-polysomnographic motor events showed differences in their occurrence throughout the night in the two groups. iRBD and RBD due to narcolepsy do have different clinical and pathological findings, confirming a different pathophysiology.

2019 - Cardiovascular autonomic dysfunction, altered sleep architecture, and muscle overactivity during nocturnal sleep in pediatric patients with narcolepsy type 1 [Articolo su rivista]
Vandi, Stefano; Rodolfi, Sara; Pizza, Fabio; Moresco, Monica; Antelmi, Elena; Ferri, Raffaele; Mignot, Emmanuel; Plazzi, Giuseppe; Silvani, Alessandro

arterial blood pressure (ABP) decreases during sleep compared to wakefulness and this change is blunted in mouse models of and adult patients with narcolepsy type 1 (NT1). We tested whether: 1) pediatric patients with NT1 have similar cardiovascular autonomic abnormalities during nocturnal sleep; and 2) these abnormalities can be linked to hypocretin-1 cerebrospinal fluid concentration (CSF HCRT-1), sleep architecture or muscle activity.

2019 - Clinical features of sleep-related hypermotor epilepsy in relation to the seizure-onset zone: A review of 135 surgically treated cases [Articolo su rivista]
Gibbs, S. A.; Proserpio, P.; Francione, S.; Mai, R.; Cardinale, F.; Sartori, I.; Castana, L.; Plazzi, G.; Tinuper, P.; Cossu, M.; Russo, G. L.; Tassi, L.; Nobili, L.

Objectives: Sleep-related hypermotor epilepsy (SHE), formerly nocturnal frontal lobe epilepsy, is characterized by abrupt and typically sleep-related seizures with motor patterns of variable complexity and duration. They seizures arise more frequently in the frontal lobe than in the extrafrontal regions but identifying the seizure onset-zone (SOZ) may be challenging. In this study, we aimed to describe the clinical features of both frontal and extrafrontal SHE, focusing on ictal semiologic patterns in order to increase diagnostic accuracy. Methods: We retrospectively analyzed the clinical features of patients with drug-resistant SHE seen in our center for epilepsy surgery. Patients were divided into frontal and extrafrontal SHE (temporal, operculoinsular, and posterior SHE). We classified seizure semiology according to four semiology patterns (SPs): elementary motor signs (SP1), unnatural hypermotor movements (SP2), integrated hypermotor movements (SP3), and gestural behaviors with high emotional content (SP4). Early nonmotor manifestations were also assessed. Results: Our case series consisted of 91 frontal SHE and 44 extrafrontal SHE cases. Frontal and extrafrontal SHE shared many features such as young age at onset, high seizure-frequency rate, high rate of scalp electroencephalography (EEG) and magnetic resonance imaging (MRI) abnormalities, similar histopathologic substrates, and good postsurgical outcome. Within the frontal lobe, SPs were organized in a posteroanterior gradient (SP1-4) with respect to the SOZ. In temporal SHE, SP1 was rare and SP3-4 frequent, whereas in operculoinsular and posterior SHE, SP4 was absent. Nonmotor manifestations were frequent (70%) and some could provide valuable localizing information. Significance: Our study shows that the presence of certain SP and nonmotor manifestations may provide helpful information to localize seizure onset in patients with SHE.

2019 - Correction: Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases [Articolo su rivista]
Luo, G.; Lin, L.; Jacob, L.; Bonvalet, M.; Ambati, A.; Plazzi, G.; Pizza, F.; Leib, R.; Adams, C. M.; Partinen, M.; Mignot, E. J. -M.

Following publication of this [1] article, questions were raised about some of the reported methods and results, and about differences between the findings reported in this article and in a previous article published by another group [2]. The PLOS ONE Editors reviewed this matter, and consider that the research reported in the PLOS ONE article is scientifically valid and meets the journal’s publication criteria, but that some items require clarification and additional controls. The authors address these issues below: “As noted in [1], we were unable to replicate some findings reported by Ahmed et al. in [2]. We would like to provide some clarifications regarding some methodological differences between the two studies. First, a statement in the Discussion was inaccurate in relaying the differences between the results of peptide binding affinity to DQ0602. The statement: ‘The fact that NP 111-121 (YDKEEIRRIWR) (116I was underlined) and HCRTR2 34-45 (YDDEEFLRYLWR) did not appear to bind to DQ0602 (unlike what was reported with the Proimmune 1 array by Ahmed et al. [43]) (Fig 2, S19 Table) suggested this epitope was likely irrelevant to DQ0602-associated narcolepsy or differential vaccine risk’ should instead read: The fact that NP 111-121 (YDKEEIR RIWR) (116I was underlined) and HCRTR2 34-45 (YDDEEFLRYLWR) did not appear to bind to DQ0602 (Competition binding results S23 Table this Correction) (Of note, ‘NP109-113 116I’ of Fig 2 in [1] should be corrected to ‘NP109-123 116I’) suggested this HCRTR2 epitope was likely irrelevant to DQ0602-associated narcolepsy or differential vaccine risk. Indeed, S3 Table of Ahmed and Steinman’s Proimmune REVEAL 1 data [2] showed weak binding for RELILYDKEEIRRIWRQANNG (24.4 and 16.9 of REVEAL 1 score at first measure and post 24h, respectively), little binding for RELILYDKEEMRRIWRQANNG (1.5 and 0.5 of REVEAL 1 score at first measure and post 24h, respectively) and no binding for the HCRTR2 peptide (LNPTDYDDEEFLRYLWREYLH) (0.0 of REVEAL 1 score at both first measure and post 24h). We overlooked these small differences. Our results show little binding for RELI LYDKEEIRRIWRQANNG (92.40±2.33% of Bio-EBV binding), very weak binding for RELI LYDKEEMRRIWRQANNG (77.84±1.10% of Bio-EBV binding) and no binding for the HCRTR2 34-45 peptide (98.12±1.38% or 99.85±2.10% of Bio-EBV binding) (competition binding results S23 Table this Correction). This does not change our interpretation. Second, intrigued by the results reported by Ahmed et al. [2], we also conducted our own peptide binding studies to DQ0602 using the Proimmune REVEAL 1 binding assay (See S1 File of this Correction) and compared these results for 144 peptides with our own competition assay that uses DQ0602 monomers bound to Bio-EBV (more than 1,446 peptides have been tested using this platform). Results are shown in S12 Fig this Correction S23 Table this Correction; underlying data and analyses are provided in S2 File of this Correction. Overall, no significant correlation was found between our competition binding assay using Bio-EBV and Proimmune results (r 2 = 0.00795, p = 0.290 at 0h; r 2 = 0.00026, p = 0.848 at S12 Fig this Correction). Classifying our binders into strong (high displacement, 25% of Bio-EBV binding) or weak binders (partial displacement, 25–50% of Bio-EBV binding) in our competition assay and positive versus negative in the Proimmune assay also did not reveal any correlation using χ 2 (all p values>0.56, S2 File of this Correction). Further illustrating this, the known EBV binding epitope of DQ0602 (EBV 486-500 ) [6–8], which was used in our competition binding assay, and HA 273-287 , a strong binder in our assay (8.10±1.53% of Bio-EBV S23 Table this Correction), were found not to bind to DQ0602 using the Proimmune 1 assay (0.0 of REVEAL 1 score at both 0h and post 24h, S1 File of this Correction). This led us to conclude that the Proimmune DQ0602 binding assay was unreliabl

2019 - Cortical activation during sleep predicts dream experience in narcolepsy [Articolo su rivista]
D'Atri, A.; Scarpelli, S.; Schiappa, C.; Pizza, F.; Vandi, S.; Ferrara, M.; Cipolli, C.; Plazzi, G.; De Gennaro, L.

Objective: Narcolepsy type 1 widely affects the architecture of sleep with frequent fast transition to REM sleep at both nighttime and daytime sleep onset. The occurrence of repeated sleep onset REM periods over the Multiple Sleep Latency Test offers a unique opportunity to identify EEG patterns predictive of successful dream recall after short periods composed of only REM or NREM sleep. It also permits to disentangle state- from trait-like differences in dream recall, by using a within-subjects design. Methods: A consecutive series of 115 first-diagnosed drug-free adult narcolepsy-type 1 patients underwent Multiple Sleep Latency Tests and were asked after each nap opportunity if they had or had not a dream experience. Scalp EEG power and a specific index of cortical activation (delta/beta power ratio), obtained from naps of 43 patients with both presence and absence of dream recall in the same sleep stage, were compared separately for REM and NREM sleep. Results: Successful dream recall was associated with an increased EEG desynchronization in both REM and NREM over partially overlapping cortical areas. Compared to unsuccessful recall, it showed (1) lower delta power over centro-parietal areas during both stages, (2) higher beta power in the same cortical areas during NREM, and (3) lower values in the delta/beta ratio during NREM in most scalp locations. Interpretation: A more activated electrophysiological milieu in both REM and NREM sleep promotes dream recall, strengthening the notion that the parietal areas are crucial not only in generating dream experience, as shown in brain-damaged patients, but also in the memory processing leading to recall.

2019 - Health-related quality of life in patients with narcolepsy: A review of the literature [Articolo su rivista]
Raggi, A.; Plazzi, G.; Ferri, R.

Narcolepsy is a chronic disorder characterized by symptoms of excessive daytime sleepiness, irresistible sleep attacks that may be accompanied by cataplexy brought on by emotions, sleep paralysis, and hypnagogic hallucinations. This is a review of 32 empirical articles on health-related quality of life (HRQoL) published in peer-reviewed journals over the past 37 years. Deleterious implications on education, recreation, driving, sexual life, and personality are associated with the disease with a consequent negative psychosocial impact. Sleepiness has an important influence on HRQoL, more than the other symptoms of this disorder that have disrupting roles, too. Therefore, patients with narcolepsy need assistance not only for medication prescription but also in terms of psychological and social support. It is also of importance to assess patients with narcolepsy carefully in terms of depressive symptoms because they may have a major impact on HRQoL with important clinical implications.

2019 - Increased creative thinking in narcolepsy [Articolo su rivista]
Lacaux, Célia; Izabelle, Charlotte; Santantonio, Giulio; De Villèle, Laure; Frain, Johanna; Lubart, Todd; Pizza, Fabio; Plazzi, Giuseppe; Arnulf, Isabelle; Oudiette, Delphine

Some studies suggest a link between creativity and rapid eye movement sleep. Narcolepsy is characterized by falling asleep directly into rapid eye movement sleep, states of dissociated wakefulness and rapid eye movement sleep (cataplexy, hypnagogic hallucinations, sleep paralysis, rapid eye movement sleep behaviour disorder and lucid dreaming) and a high dream recall frequency. Lucid dreaming (the awareness of dreaming while dreaming) has been correlated with creativity. Given their life-long privileged access to rapid eye movement sleep and dreams, we hypothesized that subjects with narcolepsy may have developed high creative abilities. To test this assumption, 185 subjects with narcolepsy and 126 healthy controls were evaluated for their level of creativity with two questionnaires, the Test of Creative Profile and the Creativity Achievement Questionnaire. Creativity was also objectively tested in 30 controls and 30 subjects with narcolepsy using the Evaluation of Potential Creativity test battery, which measures divergent and convergent modes of creative thinking in the graphic and verbal domains, using concrete and abstract problems. Subjects with narcolepsy obtained higher scores than controls on the Test of Creative Profile (mean +/- standard deviation: 58.9 +/- 9.6 versus 55.1 +/- 10, P = 0.001), in the three creative profiles (Innovative, Imaginative and Researcher) and on the Creative Achievement Questionnaire (10.4 +/- 25.7 versus 6.4 +/- 7.6, P = 0.047). They also performed better than controls on the objective test of creative performance (4.3 +/- 1.5 versus 3.7 +/- 1.4; P = 0.009). Most symptoms of narcolepsy (including sleepiness, hypnagogic hallucinations, sleep paralysis, lucid dreaming, and rapid eye movement sleep behaviour disorder, but not cataplexy) were associated with higher scores on the Test of Creative Profile. These results highlight a higher creative potential in subjects with narcolepsy and further support a role of rapid eye movement sleep in creativity.

2019 - Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations [Articolo su rivista]
Rubboli, G.; Plazzi, G.; Picard, F.; Nobili, L.; Hirsch, E.; Chelly, J.; Prayson, R. A.; Boutonnat, J.; Bramerio, M.; Kahane, P.; Dibbens, L. M.; Gardella, E.; Baulac, S.; Moller, R. S.

Mutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies.

2019 - New revolution in the assessment of cerebrospinal fluid orexin-A: Enzyme-linked immunosorbent assay! [Articolo su rivista]
Liguori, Claudio; Moresco, Monica; Izzi, Francesca; Mercuri, Nicola Biagio; Plazzi, Giuseppe; Placidi, Fabio


2019 - Persistence of limb dystonia and myoclonus during sleep in corticobasal syndrome: a case series [Articolo su rivista]
Infante, Rossella; Antelmi, Elena; Pizza, Fabio; Stanzani Maserati, Michelangelo; Plazzi, Giuseppe; Rizzo, Giovanni; Liguori, Rocco


2019 - Red Flags for early referral of people with symptoms suggestive of narcolepsy: a report from a national multidisciplinary panel [Articolo su rivista]
Vignatelli, L.; Antelmi, E.; Ceretelli, I.; Bellini, M.; Carta, C.; Cortelli, P.; Ferini-Strambi, L.; Ferri, R.; Guerrini, R.; Ingravallo, F.; Marchiani, V.; Mari, F.; Pieroni, G.; Pizza, F.; Verga, M. C.; Verrillo, E.; Taruscio, D.; Plazzi, Giuseppe

Objective: Narcolepsy is a lifelong disease, manifesting with excessive daytime sleepiness and cataplexy, arising between childhood and young adulthood. The diagnosis is typically made after a long delay that burdens the disease severity. The aim of the project, promoted by the “Associazione Italiana Narcolettici e Ipersonni” is to develop Red Flags to detect symptoms for early referral, targeting non-sleep medicine specialists, general practitioners, and pediatricians. Materials and methods: A multidisciplinary panel, including patients, public institutions, and representatives of national scientific societies of specialties possibly involved in the diagnostic process of suspected narcolepsy, was convened. The project was accomplished in three phases. Phase 1: Sleep experts shaped clinical pictures of narcolepsy in pediatric and adult patients. On the basis of these pictures, Red Flags were drafted. Phase 2: Representatives of the scientific societies and patients filled in a form to identify barriers to the diagnosis of narcolepsy. Phase 3: The panel produced suggestions for the implementation of Red Flags. Results: Red Flags were produced representing three clinical pictures of narcolepsy in pediatric patients ((1) usual sleep symptoms, (2) unusual sleep symptoms, (3) endocrinological signs) and two in adult patients ((1) usual sleep symptoms, (2) unusual sleep symptoms). Inadequate knowledge of symptoms at onset by medical doctors turned out to be the main reported barrier to diagnosis. Conclusions: This report will hopefully enhance knowledge and awareness of narcolepsy among non-specialists in sleep medicine in order to reduce the diagnostic delay that burdens patients in Italy. Similar initiatives could be promoted across Europe.

2019 - Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: A multicentre study [Articolo su rivista]
Postuma, R. B.; Iranzo, A.; Hu, M.; Hogl, B.; Boeve, B. F.; Manni, R.; Oertel, W. H.; Arnulf, I.; Ferini-Strambi, L.; Puligheddu, M.; Antelmi, E.; Cochen De Cock, V.; Arnaldi, D.; Mollenhauer, B.; Videnovic, A.; Sonka, K.; Jung, K. -Y.; Kunz, D.; Dauvilliers, Y.; Provini, F.; Lewis, S. J.; Buskova, J.; Pavlova, M.; Heidbreder, A.; Montplaisir, J. Y.; Santamaria, J.; Barber, T. R.; Stefani, A.; Louis, S. E. K.; Terzaghi, M.; Janzen, A.; Leu-Semenescu, S.; Plazzi, G.; Nobili, F.; Sixel-Doering, F.; Dusek, P.; Bes, F.; Cortelli, P.; Ehgoetz Martens, K.; Gagnon, J. -F.; Gaig, C.; Zucconi, M.; Trenkwalder, C.; Gan-Or, Z.; Lo, C.; Rolinski, M.; Mahlknecht, P.; Holzknecht, E.; Boeve, A. R.; Teigen, L. N.; Toscano, G.; Mayer, G.; Morbelli, S.; Dawson, B.; Pelletier, A.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

2019 - The neuronal network of laughing in young patients with untreated narcolepsy [Articolo su rivista]
Vaudano, Anna Elisabetta; Pizza, Fabio; Talami, Francesca; Plazzi, Giuseppe; Meletti, Stefano

To investigate the neuronal correlates of spontaneous laughter in drug-naive pediatric patients with narcolepsy type I (NT1) compared to healthy controls by means of blood oxygen level-dependent (BOLD) MRI.

2019 - Time evolution of restless legs syndrome in haemodialysis patients [Articolo su rivista]
Capelli, I; Pizza, F; Ruggeri, M; Gasperoni, L; Carretta, E; Donati, G; Cianciolo, G; Plazzi, G; La Manna, G.

Background: Restless legs syndrome (RLS) is characterized by an urge to move the extremities, accompanied by paraesthesiae, in the evening and at night. Uraemic RLS, a type of secondary RLS, occurs commonly in chronic kidney disease and end-stage renal disease. Progression of uraemic RLS over time is unclear. Therefore we investigated the prevalence, progression over time, risk factors and impact on survival of uraemic RLS in a cohort of dialysis patients. Methods: We reviewed at the 7-year follow-up a cohort of haemodialysis (HD) patients we had previously investigated for RLS, through interviews, validated questionnaires and analysis of demographic and clinical data. Results: At the 7-year follow-up, RLS was present in 16% of patients, with a persistence rate of 33%. A correlation was obtained between RLS and older age, diabetes, low albumin and low body mass index. RLS was associated with reduced overall survival (median survival of 3.3 versus 3.7 years), particularly with the continuous form of RLS (1.61 years). There was a higher incidence of myocardial infarction and peripheral vascular disease, although not reaching statistical significance. RLS patients had absolute higher scores in all quality of life domains. A large majority of study patients (96%) reported being symptom-free within a few days or weeks following kidney transplantation. Conclusions: The development of RLS, especially the continuous form, in patients undergoing HD has important consequences associated with decreased survival. Our results indicated an association between uraemic RLS and ageing, diabetes and malnutrition. Considerable efforts should be focused on the treatment of RLS, since it significantly and persistently impacts the quality of life of HD patients. Kidney transplantation could represent an effective treatment option for that RLS impacts on dialysis patients' quality of life, thus confirming the secondary nature of RLS in most HD patients.

2019 - Use and safety of nitrous oxide during lumbar puncture for the diagnosis of childhood narcolepsy [Articolo su rivista]
Testoni, C.; Sallemi, G.; Pizza, F.; Capelli, P.; Moresco, M.; Antelmi, E.; Plazzi, G.; Zanello, M.


2019 - Validation of Multiple Sleep Latency Test for the diagnosis of pediatric narcolepsy type 1 [Articolo su rivista]
Pizza, Fabio; Barateau, Lucie; Jaussent, Isabelle; Vandi, Stefano; Antelmi, Elena; Mignot, Emmanuel; Dauvilliers, Yves; Plazzi, Giuseppe

To validate polysomnographic markers (sleep latency and sleep-onset REM periods [SOREMPs] at the Multiple Sleep Latency Test [MSLT] and nocturnal polysomnography [PSG]) for pediatric narcolepsy type 1 (NT1) against CSF hypocretin-1 (hcrt-1) deficiency and presence of cataplexy, as no criteria are currently validated in children.

2018 - A provisional tool for the measurement of sleep satisfaction [Articolo su rivista]
Ohayon, Maurice M.; Chen, Michael C.; Bixler, Edward; Dauvilliers, Yves; Gozal, David; Plazzi, Giuseppe; Vitiello, Michael V.; Paskow, Michael; Roach, Anita; Hirshkowitz, Max

Objectives The goal of this project was to provisionally identify the basic elements of sleep satisfaction within the general population. Methods The National Sleep Foundation conducted a systematic literature review and identified 495 published articles evaluating potential indicators of sleep satisfaction. The National Sleep Foundation then convened an expert panel (“Panel”), provided full-text articles and summaries, and used a modified RAND appropriateness method with three total rounds of voting to determine the appropriateness of indicators for sleep satisfaction. Results The literature review revealed no tools or measures of sleep satisfaction (not dissatisfaction) applied to the general population and directly associated with good health. Nonetheless, a variety of sleep factors were extracted from the extant sleep research literature. Panel members voted on these indicators: sleep environmental factors; and sleep initiation and maintenance parameters. Using these indicators, the Panel constructed provisional questions for measuring sleep satisfaction. Conclusions The Panel determined that appropriate sleep satisfaction elements include how an individual feels (a) about their sleep, (b) immediately after their sleep, and (c) during the subsequent day. Additionally, appropriate environmental elements include (a) bedding comfort, (b) bedroom temperature, and (c) noise and light in the bedroom. How one feels with (a) the time it takes to fall asleep, (b) the ease with which one falls back to sleep after awakening during a sleep period, (c) the amount of sleep on weekdays and weekends, as well as how undisturbed one's sleep is also were determined to be appropriate contributors to sleep satisfaction. Finally, the Panel agreed that whether an individual desired to change anything about their sleep, is a relevant question.

2018 - Advantages of single step over step-by-step screening for sleep disorders [Articolo su rivista]
Tonetti, Lorenzo; Filardi, Marco; Plazzi, Giuseppe; Natale, Vincenzo

Two secondary analyses of previously collected data were carried out to detect the best screening strategy for primary insomnia (Study 1) and narcolepsy type 1 (Study 2) between two different approaches: (A) step-by-step (i.e. first step: subjective assessment through mini sleep questionnaire–MSQ; second step: objective assessment through actigraphic assessment only for those positive at the first step) and (B) single step (i.e. simultaneous subjective and objective assessment). Forty-six healthy controls (HC) and 46 primary insomnia patients (PI) were analyzed in Study 1; 40 HC and 40 narcolepsy type-1 patients (NT1) were analyzed in Study 2. All participants originally wore the Micro Motionlogger Watch actigraph (Ambulatory Monitoring, Inc., Ardlsey, NY) around the non-dominant wrist for seven consecutive days, and upon completing the actigraphic assessment filled in the MSQ. In Study 1, the single-step approach correctly identified 93.48% of PI, while only 50% of PI were correctly identified by the step-by-step approach. In Study 2, 100% of NT1 was correctly classified through the single-step approach, while 72.5% according to the step-by-step approach. The result of both studies highlights the higher appropriateness of single step (i.e. bi-dimensional assessment) compared to step-by-step approach to screen primary insomnia and narcolepsy type-1 patients.

2018 - Automatic detection of cataplexy [Articolo su rivista]
Bartolini, Ilaria; Pizza, Fabio; Di Luzio, Andrea; Neccia, Giulia; Antelmi, Elena; Vandi, Stefano; Plazzi, Giuseppe

Objective: Although being the most specific symptom of narcolepsy type 1 (NT1), cataplexy is currently investigated by clinical interview only, with potential diagnostic pitfalls. Our study aimed at testing the accuracy of an automatic video detection of cataplexy in NT1 patients vs. non-cataplectic subjects undergoing a standardized test with emotional stimulation. Methods: Fifteen drug-naive NT1 patients and 15 age- and sex-balanced non-cataplectic subjects underwent a standardized video recording procedure including emotional stimulation causing laughter. Video recordings were visually inspected by human scorers to detect three typical cataplexy facial motor patterns (ptosis, mouth opening and head drop), and then analysed by SHIATSU (Semantic-based HIearchical Automatic Tagging of videos by Segmentation using cUts). Expert-based and automatic attack detection was compared in NT1 patients and non-cataplectic subjects. Results: All NT1 patients and none of the non-cataplectic subjects displayed cataplexy during emotional stimulation. Automatic detection correlated well with experts’ assessments in NT1 with an overall accuracy of 81%. In non-cataplectic subjects, automatic detection falsely identified cataplexy in two out of 15 (13.3%) subjects who showed active eyes closure during intense laughter as a confounder with ptosis. Conclusions: Automatic cataplexy detection by applying SHIATSU to a standardized test for video documentation of cataplexy is feasible, with an overall accuracy of 81% compared to human examiners. Further studies are warranted to enlarge the range of elementary motor patterns detected, analyse their temporal/spatial relations and quantify cataplexy for diagnostic purposes.

2018 - Can smartphone sleep applications reliably assess sleep-wake cycle? Preliminary findings from a PSG study [Abstract in Atti di Convegno]
Mazzetti, M; Fino, E; Pizza, F; Vandi, S; Plazzi, G.

Objectives: Smartphone applications are considered as the prime candidate for the purposes of large scale, low cost and long term sleep monitoring. How reliable is smartphone assessment of sleep remains a key issue and more validation studies with both healthy and patient populations are needed. In this study we compared the performance of four smartphone applications (Sleep Cycle-accelerometer; Sleep Cycle-microphone; Smart Alarm; Sense) with polysomnoghraphy (PSG). Our main objective was evaluating whether sleep reports provided by applications offer reliable assessment of standard sleep parameters and establishing which of the application features result more promising for personal home use. Methods: 20 healthy participants were recorded at home, for two consecutive nights. Four iPhone applications (two per each night) designed for sleep–wake detection were used simultaneously with PSG. Results: Pearson’s correlation coefficients between PSG parameters (Time in bed, TIB; Total Sleep Time, TST; Wake After Sleep Onset, WASO; Sleep Efficiency, SE; Sleep Latency, SL; NREM Sleep Stages 1-4, N1, N2, N3, N4; Slow Wave Sleep, SWS; Rapid Eye Movement Sleep, REMS) and app reports were calculated. Significant correlations are reported below. Sense: TIB (app) and TIB (PSG): r= .713, p=.003; TST (app) and TST (PSG): r= .777, p=.001; Sleep Score (app) and SE (PSG): r= .482, p=.069; Light Sleep (app) and N1+N2+ REM (PSG): r= .424, p=.062; Sleeping Soundly(app) and N3: r= .596, p=.019; Sleeping Soundly(app) and N4(PSG): r= .520, p=.047. Smart Alarm: TIB (app) and TIB (PSG): r= .944, p< .001; Time Awake (app) and WASO (PSG): r= .473, p=.035; Sleep Quality (app) and SE(PSG): r= .431, p=.057. Sleep Cycle-accelerometer: TIB(app) and TIB (PSG): r= .672, p=.002; Sleep quality (app) and SE (PSG): r= -.480, p=.038. Sleep Cycle-microphone: TIB (app) and TIB (PSG): r= .492, p=.045; Sleep quality (app) and TIB (PSG): r= -.522, p=.032. Conclusions: Two apps provided partially reliable estimates of SE and showed significant correlations with TST and WASO measured by PSG. Only one app showed significant correlations with SWS parameters. In general, the examined apps do not offer reliable sleep stage data, not discriminating light sleep from deep sleep and especially not providing any estimate of REM.

2018 - Cerebellar and brainstem functional abnormalities in patients with primary orthostatic tremor [Articolo su rivista]
Antelmi, Elena; Rocchi, Lorenzo; Cocco, Antoniangela; Erro, Roberto; Latorre, Anna; Liguori, Rocco; Plazzi, Giuseppe; Berardelli, Alfredo; Rothwell, John; Bhatia, Kailash P


2018 - Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy [Articolo su rivista]
Gramegna, L L; Pisano, A; Testa, C; Manners, David N; D'Angelo, R; Boschetti, E; Giancola, F; Pironi, L; Caporali, L; Capristo, M; Valentino, Maria Lucia; Plazzi, G; Casali, C; Dotti, M T; Cenacchi, G; Hirano, M; Giordano, C; Parchi, P; Rinaldi, R; De Giorgio, R; Lodi, R; Carelli, V; Tonon, C

Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in thethymidine phosphorylasegene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology.

2018 - Clinical Characteristics and Burden of Illness in Pediatric Patients with Narcolepsy [Articolo su rivista]
Plazzi, Giuseppe; Clawges, Heather M.; Owens, Judith A.

Background: Narcolepsy is a chronic and lifelong neurologic disorder with onset commonly occurring in childhood or adolescence, and affecting approximately 0.025% to 0.05% of the general population. The primary symptom is excessive daytime sleepiness, which is accompanied by cataplexy in 70% of patients. Other common symptoms include sleep paralysis, hallucinations upon falling asleep or waking, and disrupted nocturnal sleep. Narcolepsy is associated with a considerable burden of illness (BOI), which has been well characterized in adults, and is exacerbated by delays in symptom recognition, diagnosis, and intervention. METHODS: This review describes the specific characteristics and BOI of pediatric narcolepsy, using a wide range of published research data. RESULTS: Pediatric narcolepsy presents distinct challenges in diagnosis and management. Narcolepsy symptoms often initially manifest differently in children and adolescents versus adults, which may pose diagnostic dilemmas. Children often respond to sleepiness with irritability, hyperactivity, and poor attention, which may be misinterpreted as misbehavior or neurocognitive sequelae of other conditions. Pediatric cataplexy symptoms may include subtle and unusual facial expressions or choreic-like movements, which are not observed in adults. Insufficient sleep and circadian rhythm disorders presenting with excessive daytime sleepiness are common in adolescents, potentially confounding narcolepsy diagnosis. Pediatric narcolepsy is also associated with comorbidities including rapid weight gain, precocious puberty, and attention deficit hyperactivity disorder, and increased risk for deficits in social functioning, depression, and anxiety. School performance is also typically impaired, requiring special education services. CONCLUSIONS: Thus, the discrete BOI of pediatric narcolepsy underscores the need for prompt and accurate diagnosis, and appropriate treatment of this disorder.

2018 - Cortical and Subcortical Brain Changes in Children and Adolescents With Narcolepsy Type 1 [Articolo su rivista]
Tondelli, Manuela; Pizza, Fabio; Vaudano, Anna Elisabetta; Plazzi, Giuseppe; Meletti, Stefano

Neuroimaging studies on structural alterations in patients with type 1 narcolepsy (NT1) have shown controversial and heterogeneous results. The purpose of this study was to investigate microstructural brain changes in patients with NT1 close to disease onset.

2018 - Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning [Articolo su rivista]
Zhang, Zhongxing; Mayer, Geert; Dauvilliers, Yves; Plazzi, Giuseppe; Pizza, Fabio; Fronczek, Rolf; Santamaria, Joan; Partinen, Markku; Overeem, Sebastiaan; Peraita-Adrados, Rosa; Da Silva, Antonio Martins; Sonka, Karel; Rio-Villegas, Rafael Del; Heinzer, Raphael; Wierzbicka, Aleksandra; Young, Peter; Högl, Birgit; Bassetti, Claudio L.; Manconi, Mauro; Feketeova, Eva; Mathis, Johannes; Paiva, Teresa; Canellas, Francesca; Lecendreux, Michel; Baumann, Christian R.; Barateau, Lucie; Pesenti, Carole; Antelmi, Elena; Gaig, Carles; Iranzo, Alex; Lillo-Triguero, Laura; Medrano-Martínez, Pablo; Haba-Rubio, José; Gorban, Corina; Luca, Gianina; Lammers, Gert Jan; Khatami, Ramin

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

2018 - Flow cytometry analysis of T-cell subsets in cerebrospinal fluid of narcolepsy type 1 patients with long-lasting disease [Articolo su rivista]
Moresco, Monica; Lecciso, Mariangela; Ocadlikova, Darina; Filardi, Marco; Melzi, Silvia; Kornum, Birgitte Rahbek; Antelmi, Elena; Pizza, Fabio; Mignot, Emmanuel; Curti, Antonio; Plazzi, Giuseppe

Background Type 1 narcolepsy (NT1) is a central hypersomnia linked to the destruction of hypocretin-producing neurons. A great body of genetic and epidemiological data points to likely autoimmune disease aetiology. Recent reports have characterized peripheral blood T-cell subsets in NT1, whereas data regarding the cerebrospinal fluid (CSF) immune cell composition are lacking. The current study aimed to characterize the T-cell and natural killer (NK) cell subsets in NT1 patients with long disease course. Methods Immune cell subsets from CSF and peripheral blood mononuclear cell (PBMC) samples were analysed by flow cytometry in two age-balanced and sex-balanced groups of 14 NT1 patients versus 14 healthy controls. The frequency of CSF cell groups was compared with PBMCs. Non-parametric tests were used for statistical analyses. Results The NT1 patients did not show significant differences of CSF immune cell subsets compared to controls, despite a trend towards higher CD4+ terminally differentiated effector memory T cells. T cells preferentially displayed a memory phenotype in the CSF compared to PBMCs. Furthermore, a reduced frequency of CD4+ terminally differentiated effector memory T cells and an increased frequency of NK CD56bright cells was observed in PBMCs from patients compared to controls. Finally, the ratio between CSF and peripheral CD4+ terminally differentiated effector memory T cells was two-fold increased in NT1 patients versus controls. Conclusions Significant differences in PBMCs and in CSF/PBMC ratios of immune cell profile were found in NT1 patients compared to healthy controls. These differences might have arisen from the different HLA status, or be primary or secondary to hypocretin deficiency. Further functional studies in patients close to disease onset are required to understand NT1 pathophysiology.

2018 - Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder [Articolo su rivista]
Li, Jiao; Ruskey, Jennifer A.; Arnulf, Isabelle; Dauvilliers, Yves; Hu, Michele T. M.; Högl, Birgit; Leblond, Claire S.; Zhou, Sirui; Ambalavanan, Amirthagowri; Ross, Jay P.; Bourassa, Cynthia V.; Spiegelman, Dan; Laurent, Sandra B; Stefani, Ambra; Charley Monaca, Christelle; Cochen De Cock, Valérie; Boivin, Michel; Ferini-Strambi, Luigi; Plazzi, Giuseppe; Antelmi, Elena; Young, Peter; Heidbreder, Anna; Labbe, Catherine; Ferman, Tanis J.; Dion, Patrick A.; Fan, Dongsheng; Desautels, Alex; Gagnon, Jean-François; Dupré, Nicolas; Fon, Edward A.; Montplaisir, Jacques Y.; Boeve, Bradley F.; Postuma, Ronald B.; Rouleau, Guy A.; Ross, Owen A.; Gan-Or, Ziv

Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. Results: MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.

2018 - GHB pharmacology and toxicology: From metabolism and pharmacokinetics to applications: Clinical and forensic toxicology [Articolo su rivista]
Busardò, Francesco Paolo; Vergallo, Gianluca M.; Plazzi, Giuseppe


2018 - Impact of acute administration of sodium oxybate on heart rate variability in children with type 1 narcolepsy [Articolo su rivista]
Antelmi, Elena; Plazzi, Giuseppe; Pizza, Fabio; Vandi, Stefano; Aricò, Debora; Ferri, Raffaele

Background: Currently, cardiovascular measurements in children affected with type 1 narcolepsy (NT1) have never been investigated, and neither have their modulation by the administration of sodium oxybate (SO). Methods: Twelve drug-naïve NT1 children (four males, eight females) with a mean age of 11 ± 3.16 years underwent a nocturnal polysomnography, at baseline and during the first night of SO administration. Data were contrasted with those recorded in 23 age-matched healthy controls. Heart rate variability (HRV) analysis was performed by analyzing the electrocardiogram signal for automatic detection of R waves with a computer program calculating a series of standard time-domain measures and obtaining spectral parameters, by means of a Fast-Fourier Transform. Results: In sleep stages N2 and N3, NT1 children showed increased power in the low-frequency (LF) and very-LF (VLF) ranges, when compared to controls. In addition, HRV (as measured by time domain parameters) during all sleep stages tended to be slightly higher in patients when compared to controls. Treatment with SO did not change significantly any parameter, but an overall trend to mildly decreased HRV that reached a significant value only during R sleep. Conclusions: HRV during all sleep stages tended to be slightly higher in young patients when compared to controls, confirming the presence of a slight sympathovagal system imbalance even in NT1 children. SO tends to decrease these values especially during REM sleep and in that regard, further studies supporting these preliminary findings and considering the long-term effects of SO on heart rate parameters are warranted.

2018 - Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells [Articolo su rivista]
Zager, Adriano; Brandã£o, Wesley Nogueira; Margatho, Rafael Oliveira; Cruz, Daniel Sanzio Gimenes; Peron, Jean Pierre; Tufik, Sergio; Andersen, Monica Levy; Moresco, Monica; Pizza, Fabio; Plazzi, Giuseppe; Kornum, Birgitte Rahbek; Palermo-neto, Joã£o

The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-γ, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-γ, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-γ producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-γ producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process.

2018 - In-field assessment of sodium oxybate effect in pediatric type 1 narcolepsy: An actigraphic study [Articolo su rivista]
Filardi, Marco; Pizza, Fabio; Antelmi, Elena; Ferri, Raffaele; Natale, Vincenzo; Plazzi, Giuseppe

Study Objectives: Sodium oxybate (SXB) is a GABAergic agent widely used as off-label treatment in pediatric type 1 narcolepsy (NT1). Here, we aimed at analyzing by wrist actigraphy the sleep/wake profile of NT1 children and adolescents in drug-naïve condition and after 1 year of SXB treatment. As secondary aim, we investigated changes on sleepiness, cataplexy, and children's anthropometric profile after 1 year of SXB treatment. Methods: Twenty-four drug-naïve NT1 children underwent 7 days of actigraphy during the school week. Information on sleepiness, narcolepsy symptoms, and anthropometric features were collected during the same week with questionnaires and semistructured clinical interview. Children started SXB treatment and underwent a second evaluation encompassing actigraphy, clinical interview, questionnaires, and anthropometric assessment after 1 year of stable treatment. Results: Actigraphy effectively documented an improvement of nocturnal sleep quality and duration coupled with a reduction of diurnal total sleep time, nap frequency, and duration at 1 year follow-up. Reduction of sleepiness, cataplexy frequency and severity, and weight loss, mainly in obese and overweight NT1 children, were also observed at the 1 year follow-up. Conclusions: Actigraphy objectively documented changes in nocturnal sleep quality and diurnal napping behavior after 1 year of SXB treatment, thus representing a valid approach to ecologically assess SXB treatment effect on NT1 children's sleep/wake profile. NT1 symptoms severity and children's anthropometric features also changed as expected. Actigraphy offers the possibility to longitudinally follow up children and has potential to become a key tool to tailor treatment in pediatric patients.

2018 - Leg Movement Activity during Sleep in School-Age Children and Adolescents: A Detailed Study in Normal Controls and Subjects with Restless Legs Syndrome and Narcolepsy Type 1 [Articolo su rivista]
Ferri, Raffaele; DelRosso, Lourdes M; Aricò, Debora; Zucconi, Marco; Ferini-Strambi, Luigi; Picchietti, Daniel L; Pizza, Fabio; Plazzi, Giuseppe; Manconi, Mauro; Bruni, Oliviero

To evaluate leg movement activity during sleep (LMS) in normal school-age children and adolescents, to eventually establish age-specific periodic LMS (PLMS) index thresholds that support the diagnosis of restless legs syndrome (RLS) and to evaluate the utility of other LMS indices.

2018 - Long-term compliance, safety, and tolerability of sodium oxybate treatment in patients with narcolepsy type 1: A postauthorization, noninterventional surveillance study [Articolo su rivista]
Mayer, Geert; Plazzi, Giuseppe; Iranzo, Álex; Ortega-Albás, Juan; Quinnell, Timothy; Pesch, Hanna; Serralheiro, Pedro; Schlit, Anne-Françoise; Wuiame, Didier; Bentz, Jürgen W. G.

Study Objectives: To evaluate adherence to sodium oxybate prescribing information for indication and dosage, patients' compliance with instructions for use, safety/tolerability in routine clinical practice, and abuse potential. Methods: A postauthorization, noninterventional surveillance study (NCT00244465) in patients who were prescribed sodium oxybate according to current practice by sleep disorders specialists. Patients were monitored for ≤18 months. Results: Overall, 749 patients were enrolled; 730 included in the intent-to-treat population (narcolepsy type 1 n = 670, other indications n = 60). We report on patients with narcolepsy type 1 (female 47.9%, mean age 39.4 years); 495/670 (73.9%) completed the study. Median dose: at start of study 4.5 g per night, 6 g per night throughout study, in two equal doses. According to the treatment compliance checklist, 35.5 per cent of patients consumed alcohol, 19.3 per cent took the medication <2 hr after food, and 27.1 per cent did not adhere to recommended time schedule, with few associated treatment-emergent adverse events (TEAEs). Incidences of higher-than-recommended doses, difficulty in preparing doses, and abuse were low. TEAEs were reported by 67.3 per cent, most frequently headache (11.6%) and nasopharyngitis (6.4%). Discontinuation due to TEAEs: 8.8 per cent. Serious TEAEs: 6.4 per cent. There were no reports of respiratory depression. No particular safety concerns were identified in pediatric or elderly patients, or those with underlying sleep apnea. Conclusions: In this large postauthorization safety study of sodium oxybate use, indication and dosage prescribing recommendations were generally followed, and most patients complied with instructions, with deviations around alcohol consumption, eating before dosing and timing. The overall safety profile was consistent with previous observations; incidence of abuse was low.

2018 - LRRK2 protective haplotype and full sequencing study in REM sleep behavior disorder [Articolo su rivista]
Ouled Amar Bencheikh, Bouchra; Ruskey, Jennifer A.; Arnulf, Isabelle; Dauvilliers, Yves; Monaca, Christelle Charley; De Cock, Valérie Cochen; Gagnon, Jean-François; Spiegelman, Dan; Hu, Michele T. M.; Högl, Birgit; Stefani, Ambra; Ferini-Strambi, Luigi; Plazzi, Giuseppe; Antelmi, Elena; Young, Peter; Heidbreder, Anna; Mollenhauer, Brit; Sixel-Döring, Friederike; Trenkwalder, Claudia; Oertel, Wolfgang; Montplaisir, Jacques Y.; Postuma, Ronald B.; Rouleau, Guy A.; Gan-Or, Ziv

Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear. Methods: The full coding sequence, exon-intron boundaries and 5′ and 3′ untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD. Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44–0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05–1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified. Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD.

2018 - Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy [Articolo su rivista]
Stephansen, Jens B.; Olesen, Alexander N.; Olsen, Mads; Ambati, Aditya; Leary, Eileen B.; Moore, Hyatt E.; Carrillo, Oscar; Lin, Ling; Han, Fang; Yan, Han; Sun, Yun L.; Dauvilliers, Yves; Scholz, Sabine; Barateau, Lucie; Hogl, Birgit; Stefani, Ambra; Hong, Seung Chul; Kim, Tae Won; Pizza, Fabio; Plazzi, Giuseppe; Vandi, Stefano; Antelmi, Elena; Perrin, Dimitri; Kuna, Samuel T.; Schweitzer, Paula K.; Kushida, Clete; Peppard, Paul E.; Sorensen, Helge B. D.; Jennum, Poul; Mignot, Emmanuel

Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph—a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.

2018 - Neuroimaging Applications in Restless Legs Syndrome [Capitolo/Saggio]
Rizzo, Giovanni; Plazzi, Giuseppe

Neuroimaging studies provide information useful to understand the pathophysiology of restless legs syndrome. Molecular PET and SPECT imaging findings mainly supported dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. Magnetic resonance imaging (MRI) studies have used different techniques. Studies using iron-sensitive sequences supported the presence of a regionally variable low brain iron content, mainly at the level of substantia nigra and thalamus. The search for brain structural or microstructural abnormalities by voxel-based morphometry, diffusion tensor imaging or cortical thickness analysis has reported none or variable findings in restless legs syndrome patients, most of them in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have substantially demonstrated activation or connectivity changes in the same networks. Magnetic resonance spectroscopy studies showed metabolic changes in the thalamus, which is a hub of these networks. In summary, neuroimaging findings in restless legs syndrome support the presence of reduction of brain iron content, of dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and of abnormalities at level of limbic/nociceptive and sensorimotor networks.

2018 - Novel biomarker signatures for idiopathic REM sleep behavior disorder: A proteomic and system biology approach [Articolo su rivista]
Mondello, Stefania; Kobeissy, Firas; Mechref, Yehia; Zhao, Jingfu; Talih, Farid R.; Cosentino, Filomena; Antelmi, Elena; Moresco, Monica; Plazzi, Giuseppe; Ferri, Raffaele

OBJECTIVE: To perform a rigorous in-depth proteomics analysis to identify circulating biomarker signatures for idiopathic REM sleep behavior disorder (RBD), capable of providing new insights into the underlying pathogenic mechanisms and putative α-synuclein-related neurodegenerative processes.METHODS: Serum samples from patients with idiopathic RBD (n = 9) and healthy controls (n = 10) were subjected to a thorough liquid chromatography-mass spectrometry (MS)/MS proteomics analysis using ultimate 3,000 nanoLC interfaced to an ESI-orbitrap velos. Data were analyzed with a systems biology approach to identify altered pathways in RBD.RESULTS: We identified 259 proteins, 11 of which displayed significantly altered expression level in patients with RBD as compared to controls. Significant reduction in serum levels of dopamine β-hydroxylase (DBH) and vitamin D binding protein (GC) were consistent with alterations in the norepinephrinergic (NErgic) and dopaminergic systems, respectively. Additional altered protein profiles indicated that immunity, inflammation, complement, and coagulation also play a role in RBD pathophysiology.CONCLUSIONS: Our results shed light on the protein signature profile, molecular pathways, and mechanisms involved in the pathogenesis of RBD and its clinical manifestation. This knowledge opens a new avenue towards more accurate and timely diagnosis and characterization of RBD, which might ultimately translate into new therapeutic strategies with disease-modifying effects. Further evaluation of the identified markers is required to confirm their diagnostic value and potential to guide clinical decision-making.

2018 - Persistence of deep-tendon reflexes during partial cataplexy [Articolo su rivista]
Barateau, Lucie; Pizza, Fabio; Lopez, Régis; Antelmi, Elena; Plazzi, Giuseppe; Dauvilliers, Yves

Objective: Deep-tendon reflexes are abolished during generalized cataplexy, but whether this is the case in partial cataplexy currently remains unknown. Partial cataplexy may mimic other neurologic/psychiatric phenomena, and knowledge of the reflexes status may provide information for differential diagnosis. We assessed whether deep-tendon reflexes are persistent during partial cataplexy. Methods: Five drug-free patients with typical diagnoses of narcolepsy and clear-cut partial cataplexy were diagnosed in Reference Narcolepsy Centers in France and Italy. Biceps and patellar reflexes were elicited by physicians in charge and video-documented during cataplexy. Reflexes were assessed several times for each patient in different conditions and for various localizations of cataplexy. Results: The absence of tendon reflexes and complete loss of muscle tone during generalized cataplexy was confirmed, but the persistence of those reflexes during several partial cataplectic attacks at different ages, gender, localization of cataplexy (upper limbs, face) and reflexes (biceps, patellar) in drug-naive or withdrawal conditions was documented. Conclusion: The persistence of tendon reflexes during several partial cataplexy episodes contrasts with their absence during generalized cataplexy. This discovery has clinical implications: the persistence of tendon reflexes does not rule out cataplexy diagnosis for partial attacks, whereas their transient abolishment or persistence during generalized attacks indicates cataplexy or pseudocataplexy, respectively.

2018 - Physical activity and sleep/wake behavior, anthropometric, and metabolic profile in pediatric narcolepsy type 1 [Articolo su rivista]
Filardi, Marco; Pizza, Fabio; Antelmi, Elena; Pillastrini, Paolo; Natale, Vincenzo; Plazzi, Giuseppe

Objectives: Regular physical activity is routinely recommended in children and adolescents suffering from narcolepsy type 1 (NT1), but controlled studies analyzing its influence on sleep/wake behavior, metabolic, and anthropometric profile in pediatric NT1 are lacking. Methods: Fifty consecutive drug-naïve NT1 children and adolescents were assessed through actigraphic, clinical, and metabolic evaluations. Patients were compared with respect to their engagement in leisure-time physical activities (LTPA): patients engaged in LTPA (n = 30) and patients not engaged (No-LTPA, n = 20), respectively. Results: LTPA patients presented lower BMI, with different BMI categories distribution and higher HDL cholesterol, when compared with No-LTPA subjects. Increased night-sleep duration, higher sleep quality, and reduction of nap frequency were documented through actigraphy in LTPA subjects. Subjective sleepiness, as measured by ESS-CHAD, was also lower in LTPA subjects while cataplexy frequency proved similar between the two groups. Discussion: In pediatric NT1 patients, regular engagement in LTPA is associated with significant differences on sleepiness, anthropometric and metabolic profile and objectively assessed sleep/wake behavior. Engagement in LTPA is beneficial and should be strongly encouraged in pediatric NT1 patients.

2018 - REM sleep behavior disorder in narcolepsy [Capitolo/Saggio]
Plazzi, G.

2018 - REM sleep behaviour disorder [Articolo su rivista]
Dauvilliers, Yves; Schenck, Carlos H.; Postuma, Ronald B.; Iranzo, Alex; Luppi, Pierre-Herve; Plazzi, Giuseppe; Montplaisir, Jacques; Boeve, Bradley

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia that is characterized by loss of muscle atonia during REM sleep (known as REM sleep without atonia, or RSWA) and abnormal behaviours occurring during REM sleep, often as dream enactments that can cause injury. RBD is categorized as either idiopathic RBD or symptomatic (also known as secondary) RBD; the latter is associated with antidepressant use or with neurological diseases, especially α-synucleinopathies (such as Parkinson disease, dementia with Lewy bodies and multiple system atrophy) but also narcolepsy type 1. A clinical history of dream enactment or complex motor behaviours together with the presence of muscle activity during REM sleep confirmed by video polysomnography are mandatory for a definite RBD diagnosis. Management involves clonazepam and/or melatonin and counselling and aims to suppress unpleasant dreams and behaviours and improve bedpartner quality of life. RSWA and RBD are now recognized as manifestations of an α-synucleinopathy; most older adults with idiopathic RBD will eventually develop an overt neurodegenerative syndrome. In the future, studies will likely evaluate neuroprotective therapies in patients with idiopathic RBD to prevent or delay α-synucleinopathy-related motor and cognitive decline.

2018 - Segmental hair testing of triazolam to unmask a suspected case of idiopathic recurrent Stupor [Articolo su rivista]
Postiglione, Emanuela; Antelmi, Elena; Moresco, Monica; Pichini, Simona; Pizza, Fabio; Plazzi, Giuseppe; Busardò, Francesco Paolo

Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to "endozepine-4" accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior.

2018 - Sexsomnia: a diagnostic challenge, a case report [Articolo su rivista]
Mioč, Marina; Antelmi, Elena; Filardi, Marco; Pizza, Fabio; Ingravallo, Francesca; Nobili, Lino; Tassinari, Carlo Alberto; Schenck, Carlos H; Plazzi, Giuseppe

Sexsomnia is a parasomnia mostly associated with sexual behavior arising from NREM sleep...

2018 - Sodium oxybate treatment in pediatric type 1 narcolepsy [Articolo su rivista]
Moresco, Monica; Pizza, Fabio; Antelmi, Elena; Plazzi, Giuseppe

Background: Narcolepsy type 1 (NT1) is a chronic neurologic disorder defined by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, typically with onset during child-hood/adolescence. Pediatric NT1 is associated with limitations on children’s activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. Sodium oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid and is greatly effective in treating cataplexy and excessive daytime sleepiness in NT1 and it can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients. Method: We conducted a research of literature into bibliographic databases regarding NT1 features in childhood and the possible option treatment with SO in this kind of patient population. Results: We reported sixteen papers focusing on symptom presentation and on clinical and metabolic features of children affected with NT1. Furthermore, we reported 24 manuscripts focusing on SO biological actions and pharmacological properties and on the few but important available studies (8) conducted in NT1 children under SO therapy. Conclusion: Although in the majority of patients develop NT1 during childhood, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Ongoing pediatric therapy is based only on observational data shared among sleep disorders clinicians.

2018 - Status dissociatus and its relation to RBD [Capitolo/Saggio]
Antelmi, E.; Plazzi, G.

2018 - The clinical spectrum of childhood narcolepsy [Articolo su rivista]
Postiglione, Emanuela; Antelmi, Elena; Pizza, Fabio; Lecendreux, Michel; Dauvilliers, Yves; Plazzi, Giuseppe

Narcolepsy type 1 is a life-long, severe, multifaceted disease often arising in childhood or adolescence. Beyond the classical symptoms (excessive daytime sleepiness, cataplexy, hallucinations, sleep paralysis and nocturnal fragmented sleep), metabolic, endocrinological, psychiatric and psychosocial aspects must be considered. Despite the increased awareness after H1N1 pandemic influenza and vaccination, narcolepsy is still misdiagnosed and unrecognized. The peculiar presentation of symptoms in narcoleptic children could in part explain the misdiagnoses. Excessive daytime sleepiness presenting as chronic drowsiness or irritability could be stigmatized as laziness or misinterpreted as behavior or inattention disorder. The persistent hypotonia and the complex hyperkinetic movements that characterize cataplexy close to the onset, could be misdiagnosed as a movement disorder or as other neurologic conditions. The consequent therapeutic delay could turn into dramatic consequences. The narcolepsy onset, indeed, is associated with abrupt weight gain and sometimes with precocious puberty that require a prompt recognition and treatment to avoid auxological and metabolic complications. Moreover, narcoleptic children could have behavioral and psychiatric disorders ranging from mood to psychotic ones that need ad hoc management. Accordingly, spreading the awareness outside the sleep specialist community is necessary in order to reduce the diagnostic delay and to obtain prompt and multidisciplinary management.

2018 - The Distinguishing Motor Features of Cataplexy: A Study from Video Recorded Attacks [Articolo su rivista]
Pizza, Fabio; Antelmi, Elena; Vandi, Stefano; Meletti, Stefano; Erro, Roberto; Baumann, Christian R; Bhatia, Kailash P; Dauvilliers, Yves; Edwards, Mark J; Iranzo, Alex; Overeem, Sebastiaan; Tinazzi, Michele; Liguori, Rocco; Plazzi, Giuseppe

To describe the motor pattern of cataplexy and to determine its phenomenological differences from pseudocataplexy in the differential diagnosis of episodic falls.

2018 - The MSLT is repeatable in narcolepsy type 1 but not narcolepsy type 2: A retrospective patient study [Articolo su rivista]
Ruoff, Chad; Pizza, Fabio; Trotti, Lynn Marie; Sonka, Karel; Vandi, Stefano; Cheung, Joseph; Pinto, Swaroop; Einen, Mali; Simakajornboon, Narong; Han, Fang; Peppard, Paul; Nevsimalova, Sona; Plazzi, Giuseppe; Rye, David; Mignot, Emmanuel

Study Objectives: To examine repeatability of Multiple Sleep Latency Test (MSLT) results in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) according to the criteria of the International Classification of Sleep Disorders, Third Edition (ICSD-3). Methods: Repeatability of the MSLT was retrospectively evaluated in NT1 (n = 60) and NT2 (n = 54) cases, and controls (n = 15). All subjects had documented HLA-DQB1. 06:02 status and/or hypocretin-1 levels from cerebrospinal fluid. All subjects had undergone 2 MSLTs (≥ 1 meeting ICSD-3 criteria for narcolepsy). Repeatability was explored in children versus adults and in those on versus not on medication(s). Subsample and multivariate analysis were performed. Results: Both MSLTs in unmedicated patients were positive for narcolepsy in 78%, 18%, and 7% of NT1, NT2, and controls, respectively. NT2 cases changed to idiopathic hypersomnia or to a negative MSLT 26% and 57% of the time, respectively. Although NT1 cases were 10 to 14 times more likely to demonstrate a second positive MSLT compared to NT2 cases (P < 10-5) and controls (P < 10-4), respectively, NT2 cases were not significantly different from controls (P = .64). Medication use (P = .009) but not adult versus children status (P = .85) significantly decreased the likelihood of a repeat positive MSLT. Conclusions: In a clinical setting, a positive MSLT for narcolepsy is a more reproducible and stable feature in NT1 than NT2. The retrospective design of this study hinders interpretation of these data, as there are many different, and possibly opposing, reasons to repeat a MSLT in NT1 versus NT2 (ie, ascertainment bias). Additional systematic MSLT repeatability studies independent of confounds are ideally needed to confirm these findings.

2018 - Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation [Articolo su rivista]
Plazzi, Giuseppe; Ruoff, Chad; Lecendreux, Michel; Dauvilliers, Yves; Rosen, Carol L; Black, Jed; Parvataneni, Rupa; Guinta, Diane; Wang, Youyu Grace; Mignot, Emmanuel

Background: Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy. Methods: This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7–16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with, number NCT02221869. Findings: Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [–1·0, 2·5]; p&lt;0·0001). Commonly reported (&gt;5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths. Interpretation: These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients. Funding: Jazz Pharmaceuticals.

2018 - Type 1 narcolepsy in anti-Hu antibodies mediated encephalitis: a case report [Articolo su rivista]
Vitiello, Maria; Antelmi, Elena; Pizza, Fabio; Postiglione, Emanuela; Poggi, Rosalba; Liguori, Rocco; Plazzi, Giuseppe


2017 - Absence of anti-hypocretin receptor 2 autoantibodies in post pandemrix narcolepsy cases [Articolo su rivista]
Luo, Guo; Lin, Ling; Jacob, Louis; Bonvalet, Mã©lodie; Ambati, Aditya; Plazzi, Giuseppe; Pizza, Fabio; Leib, Ryan; Adams, Christopher M.; Partinen, Markku; Mignot, Emmanuel Jean-Marie

Background: A recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies. Methods: MS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosor-bent assay (ELISA). Results: NP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123(ILYDKEEIRRIWRQA), a mimic to HCRTR234-45(YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found positive for anti-HCRTR2 autoantibodies using two strategies or the third one, respectively. None of the post Pandemrix® narcolepsy cases (0 of 40 sera) was found positive with all three strategies. Conclusion: Anti-HCRTR2 autoantibody is not a significant biological feature of narcolepsy or of post Pandemrix® autoimmune responses.

2017 - Antibodies against hypocretin receptor 2 are rare in narcolepsy [Articolo su rivista]
Giannoccaro, Maria Pia; Waters, Patrick; Pizza, Fabio; Liguori, Rocco; Plazzi, Giuseppe; Vincent, Angela

Recently, antibodies to the hypocretin receptor 2 (HCRTR2-Abs) were reported in a high proportion of narcolepsy patients who developed the disease following Pandemrix® vaccination. We tested a group of narcolepsy patients for the HCRTR2-Abs using a newly established cell-based assay.

2017 - Aspects of functioning in people with narcolepsy identified by the ICF core set for sleep disorders: preliminary results [Abstract in Rivista]
Govi, A; Pizza, F; Plazzi, G; Ingravallo, F

2017 - Attention impairments and ADHD symptoms in adult narcoleptic patients with and without hypocretin deficiency [Articolo su rivista]
Filardi, Marco; Pizza, Fabio; Tonetti, Lorenzo; Antelmi, Elena; Natale, Vincenzo; Plazzi, Giuseppe

Background Attentional complaints are common in narcolepsy patients and can overlap with daytime sleepiness features. Few studies attempted to characterize attentional domains in narcolepsy leading to controversial results. We aimed to assess the impact of hypocretin deficiency on attentional functioning by comparing performances on the attention network test (ANT) of narcoleptic patients with hypocretin deficiency (narcolepsy type 1ÐNT1) versus patients without hypocretin deficiency (narcolepsy type 2ÐNT2) and healthy controls. We also addressed frequency and severity of psychopathological symptoms and their influence on performances on ANT. Methods Twenty-one NT1 patients, fifteen NT2 patients and twenty-two healthy controls underwent the ANT, which allows assessing three separate attentional processes (alerting, orienting and executive control), and a psychometric assessment including questionnaires on attention- deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, anxiety and depression symptoms. Results NT1 and NT2 patients presented with slower reaction times compared to controls. NT1 patients exhibited an impairment of alerting network relative to NT2 and healthy controls, while orienting and executive control networks efficiency were comparable between groups. NT1 and NT2 displayed higher severity of ADHD inattentive domain than controls, NT1 patients also displayed higher severity of ADHD hyperactive domain and depressive symptoms. In NT1, ADHD and depressive symptoms were positively correlated. Conclusions Despite a shared slowing of reaction times in both NT1 and NT2, a selective impairment of alerting network was present only in hypocretin deficient patients. Clinicians should carefully consider attentional deficits and psychopathological symptoms, including ADHD symptoms, in the clinical assessment and management of patients with narcolepsy.

2017 - Beyond the neuropsychology of dreaming: Insights into the neural basis of dreaming with new techniques of sleep recording and analysis [Articolo su rivista]
Cipolli, Carlo; Ferrara, Michele; DE GENNARO, Luigi; Plazzi, Giuseppe

Recent advances in electrophysiological [e.g., surface high-density electroencephalographic (hd-EEG) and intracranial recordings], video-polysomnography (video-PSG), transcranial stimulation and neuroimaging techniques allow more in-depth and more accurate investigation of the neural correlates of dreaming in healthy individuals and in patients with brain-damage, neurodegenerative diseases, sleep disorders or parasomnias. Convergent evidence provided by studies using these techniques in healthy subjects has led to a reformulation of several unresolved issues of dream generation and recall [such as the inter- and intra-individual differences in dream recall and the predictivity of specific EEG rhythms, such as theta in rapid eye movement (REM) sleep, for dream recall] within more comprehensive models of human consciousness and its variations across sleep/wake states than the traditional models, which were largely based on the neurophysiology of REM sleep in animals. These studies are casting new light on the neural bases (in particular, the activity of dorsal medial prefrontal cortex regions and hippocampus and amygdala areas) of the inter- and intra-individual differences in dream recall, the temporal location of specific contents or properties (e.g., lucidity) of dream experience and the processing of memories accessed during sleep and incorporated into dream content. Hd-EEG techniques, used on their own or in combination with neuroimaging, appear able to provide further important insights into how the brain generates not only dreaming during sleep but also some dreamlike experiences in waking.

2017 - Head drops: electromyography may give the way [Articolo su rivista]
Antelmi, Elena; Plazzi, Giuseppe


2017 - Incidence of sudden unexpected death in epilepsy in sleep-related hypermotor epilepsy, formerly named nocturnal frontal lobe epilepsy [Articolo su rivista]
Mostacci, Barbara; Bisulli, Francesca; Vignatelli, Luca; Licchetta, Laura; Di Vito, Lidia; Rinaldi, Claudia; Trippi, Irene; Ferri, Lorenzo; Plazzi, Giuseppe; Provini, Federica; Tinuper, Paolo


2017 - Modulation of the muscle activity during sleep in cervical dystonia [Articolo su rivista]
Antelmi, Elena; Ferri, Raffaele; Provini, Federica; Scaglione, Cesa M. L.; Mignani, Francesco; Rundo, Francesco; Vandi, Stefano; Fabbri, Margherita; Pizza, Fabio; Plazzi, Giuseppe; Martinelli, Paolo; Liguori, Rocco

Introduction: Impaired sleep has been reported as an important nonmotor feature in dystonia, but so far, self-reported complaints have never been compared with nocturnal video-polysomnographic (PSG) recording, which is the gold standard to assess sleep-related disorders. Methods: Twenty patients with idiopathic isolated cervical dystonia and 22 healthy controls (HC) underwent extensive clinical investigations, neurological examination, and questionnaire screening for excessive daytime sleepiness and sleep-related disorders. A full-night video PSG was performed in both patients and HC. An ad hoc montage, adding electromyographic leads over the muscle affected with dystonia, was used. Results: When compared to controls, patients showed significantly increased pathological values on the scale assessing self-reported complaints of impaired nocturnal sleep. Higher scores of impaired nocturnal sleep did not correlate with any clinical descriptors but for a weak correlation with higher scores on the scale for depression. On video-PSG, patients had significantly affected sleep architecture (with decreased sleep efficiency and increased sleep latency). Activity over cervical muscles disappears during all the sleep stages, reaching significantly decreased values when compared to controls both in nonrapid eye movements and rapid eye movements sleep. Conclusions: Patients with cervical dystonia reported poor sleep quality and showed impaired sleep architecture. These features however cannot be related to the persistence of muscle activity over the cervical muscles, which disappears in all the sleep stages, reaching significantly decreased values when compared to HC.

2017 - Muscle Activity During Sleep in Human Subjects, Rats, and Mice: Towards Translational Models of REM Sleep Without Atonia [Articolo su rivista]
Silvani, Alessandro; Ferri, Raffaele; LO MARTIRE, VIVIANA CARMEN; Bastianini, Stefano; Berteotti, Chiara; Salvadè, Agnese; Plazzi, Giuseppe; Zucconi, Marco; Ferini Strambi, Luigi; Bassetti, Claudio L; Manconi, Mauro; Zoccoli, Giovanna

Rapid-eye-movement (REM) sleep without atonia (RSWA) is a marker of REM sleep behavior disorder (RBD) and is common in narcolepsy. Available techniques for electromyogram (EMG) analysis are species-specific, limiting translational research on RSWA. We developed an automated technique based on distributions of normalized EMG values (DNE) to overcome this limitation. With DNE, we tested whether the control of neck and tibialis anterior (TA) muscles during sleep in wild-type rats and mice validly models the control of submentalis (chin) and TA muscles in healthy humans. We then applied DNE to REM sleep recordings of patients with idiopathic RBD and of mouse models of narcolepsy, testing for a common DNE signature of RSWA.

2017 - National Sleep Foundation's sleep quality recommendations: first report [Articolo su rivista]
Ohayon, Maurice; Wickwire, Emerson M.; Hirshkowitz, Max; Albert, Steven M.; Avidan, Alon; Daly, Frank J.; Dauvilliers, Yves; Ferri, Raffaele; Fung, Constance; Gozal, David; Hazen, Nancy; Krystal, Andrew; Lichstein, Kenneth; Mallampalli, Monica; Plazzi, Giuseppe; Rawding, Robert; Scheer, Frank A.; Somers, Virend; Vitiello, Michael V.

Objectives To provide evidence-based recommendations and guidance to the public regarding indicators of good sleep quality across the life-span. Methods The National Sleep Foundation assembled a panel of experts from the sleep community and representatives appointed by stakeholder organizations (Sleep Quality Consensus Panel). A systematic literature review identified &nbsp;277 studies meeting inclusion criteria. Abstracts and full-text articles were provided to the panelists for review and discussion. A modified Delphi RAND/UCLA Appropriateness Method with 3 rounds of voting was used to determine agreement. Results For most of the sleep continuity variables (sleep latency, number of awakenings &gt;5&nbsp;minutes, wake after sleep onset, and sleep efficiency), the panel members agreed that these measures were appropriate indicators of good sleep quality across the life-span. However, overall, there was less or no consensus regarding sleep architecture or nap-related variables as elements of good sleep quality. Conclusions There is consensus among experts regarding some indicators of sleep quality among otherwise healthy individuals. Education and public health initiatives regarding good sleep quality will require sustained and collaborative efforts from multiple stakeholders. Future research should explore how sleep architecture and naps relate to sleep quality. Implications and limitations of the consensus recommendations are discussed.

2017 - Non-24-hour sleep-wake rhythm disorder and melatonin secretion impairment in a patient with pineal cyst [Articolo su rivista]
Ferri, Lorenzo; Filardi, Marco; Moresco, Monica; Pizza, Fabio; Vandi, Stefano; Antelmi, Elena; Toni, Francesco; Zucchelli, Mino; Pierangeli, Giulia; Plazzi, Giuseppe

We report the case of a 14-year-old girl with a wide non-compressive pineal cyst, associated with the inability to control her sleep-wake schedule. Actigraphic monitoring showed a 24-hour free-running disorder (tau 26.96 hours). A 24-hour serum melatonin curve assay, with concomitant video-polysomnographic and body-core temperature monitoring, was performed. Melatonin curve showed a blunted nocturnal peak, lower total quantity of melatonin, and prolonged melatonin secretion in the morning, with normal temperature profile and sleep parameters. Treatment with melatonin up to 14 mg at bedtime was initiated with complete realignment of the sleep-wake rhythm (tau 23.93 hours). The role of the pineal cyst in the aforementioned alteration of melatonin secretion and free-running disorder remains controversial, but our case supports the utility of monitoring sleep/wake, temperature, and melatonin rhythms in the diagnostic work-up of pineal cysts associated with free-running disorder.

2017 - Parental fitness questioned on the grounds of narcolepsy: Presentation of two cases [Articolo su rivista]
Barbero, Laura; Govi, Annamaria; Pizza, Fabio; Plazzi, Giuseppe; Ingravallo, Francesca

We report two cases of fathers whose parental fitness was questioned during divorce and custody litigation because of narcolepsy type 2 and type 1, respectively. These cases highlighted both the existence of a narcolepsy-related stigma and the need to involve sleep experts in custody assessments when concerns about the parental fitness are related to a sleep disorder, expanding the field of interest of the growing “sleep forensics".

2017 - REM Sleep EEG Instability in REM Sleep Behavior Disorder and Clonazepam Effects [Articolo su rivista]
Ferri, Raffaele; Rundo, Francesco; Silvani, Alessandro; Zucconi, Marco; Bruni, Oliviero; Ferini Strambi, Luigi; Plazzi, Giuseppe; Manconi, Mauro

STUDY OBJECTIVES: We aimed to analyze quantitatively rapid eye movement (REM) sleep electroencephalogram (EEG) in controls, drug-naïve idiopathic REM sleep behavior disorder patients (iRBD), and iRBD patients treated with clonazepam. METHODS: Twenty-nine drug-naïve iRBD patients (mean age 68.2 years), 14 iRBD patients under chronic clonazepam therapy (mean age 66.3 years), and 21 controls (mean age 66.8 years) were recruited. Power spectra were obtained from sleep EEG (central derivation), using a 2-second sliding window, with 1-second steps. The power values of each REM sleep EEG spectral band (one every second) were normalized with respect to the average power value obtained during sleep stage 2 in the same individual. RESULTS: In drug-naïve patients, the normalized power values showed a less pronounced REM-related decrease of power in all bands with frequency &lt;15 Hz than controls and an increase in the beta band, negatively correlated with muscle atonia; in patients treated with clonazepam there was a partial return of all bands &lt;15 Hz toward the control values. The standard deviation values of the normalized power were higher for untreated patients in all EEG bands and were almost completely normalized in patients treated with clonazepam. CONCLUSIONS: The REM sleep EEG structure changes found in this study disclose subtle but significant alterations in the cortical electrophysiology of RBD that might represent the early expression of the supposed neurodegenerative processes already taking place at this stage of the disease and might be the target of better and effective future therapeutic strategies for this condition.

2017 - Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder [Articolo su rivista]
Antelmi, Elena; Donadio, Vincenzo; Incensi, Alex; Plazzi, Giuseppe; Liguori, Rocco

To test if phosphorylated α-synuclein (p-α-syn) deposits can be detected by means of skin biopsy in patients with idiopathic REM sleep behavior disorder (iRBD) as a potential early histopathologic marker of impending synucleinopathy.

2017 - Sleep-related hypermotor epilepsy: Long-term outcome in a large cohort [Articolo su rivista]
Licchetta, Laura; Bisulli, Francesca; Vignatelli, Luca; Zenesini, Corrado; Di Vito, Lidia; Mostacci, Barbara; Rinaldi, Claudia; Trippi, Irene; Naldi, Ilaria; Plazzi, Giuseppe; Provini, Federica; Tinuper, Paolo

To assess the long-term outcome of sleep-related hypermotor epilepsy (SHE).

2017 - Sodium oxybate for idiopathic REM sleep behavior disorder: a report on two patients [Articolo su rivista]
Moghadam Keivan, Kaveh; Pizza, Fabio; Primavera, Alberto; Ferri, Raffaele; Plazzi, Giuseppe

Background REM-sleep behavior disorder (RBD) therapy is based on small to medium-sized case series, as no large controlled clinical trials have been performed. The most used and widely recognized effective drugs are clonazepam and melatonin, with anecdotal reports on the potential benefit of other drug classes. Methods We report on two patients suffering from idiopathic RBD presenting with almost nightly complex and violent episodes, refractory to conventional drugs. Both patients, after informed consent, were treated off-label with sodium oxybate in add-on therapy. We followed up the patients in order to assess treatment efficacy by means of clinical interview, visual analog scales (VAS) for frequency and severity, Clinical Global Impression (CGI) improvement scale and efficacy index, video-polysomnography and at-home actigraphy. Results Sodium oxybate intake was well tolerated and effective in reducing the number and intensity of RBD episodes; patients reported no new traumatic episodes. Results were confirmed by bed-partner reports, VAS, CGI improvement scale and efficacy index, and at-home actigraphic monitoring, the latter showing a trend of improvement in nocturnal sleep quality and reduction in motor activity, compared to the baseline. Nevertheless, video-polysomnography did not show a clear beneficial effect on sleep-related electromyographic parameters. Conclusions Our cases suggest that sodium oxybate can be an effective add-on option for the treatment of idiopathic RBD refractory to conventional therapies. The lack of improvement of polysomnographic parameters suggests caution in considering only polysomnographic data as endpoints in the assessment of the efficacy of therapies for RBD, and that long-term home-based assessment seems a promising tool.

2017 - Spectral electroencephalography profile of rapid eye movement sleep at sleep onset in narcolepsy type 1 [Articolo su rivista]
Pizza, Fabio; Ferri, R.; Vandi, Stefano; Rundo, F.; Iloti, Martina; Neccia, G.; Plazzi, Giuseppe

Background and purpose: The sleep-onset rapid eye movement (REM) period (SOREMP), the hallmark of narcolepsy, may be a specific state and not the simple anticipation of REM sleep. Methods: We analyzed the electroencephalographic spectral content in untreated patients with narcolepsy type 1 (NT1) during the sleep-onset period (SOP) and during nocturnal REM sleep in two consecutive nocturnal recordings from 31 patients with NT1 (mean age 34 ± 15 years, 18 males) and a single nocturnal recording from 36 controls (mean age 38 ± 13 years, 21 males). The SOP was defined as the first 10 min starting at the beginning of the first epoch of any sleep stage, and further divided into two consecutive 5-min periods (SOP-1 and SOP-2); 1 min of artifact-free quiet wakefulness after lights-off was identified as well as 5 min of REM sleep in the middle of the night and another 5 min during the last REM sleep period. Electroencephalographic spectral analysis was performed using the C3/A2 channel. Results: The SOP-1 and, more strikingly, SOP-2 had significantly less delta and sigma activity in patients with NT1 in the SOREMP condition versus both controls and patients with NT1 without SOREMP. SOP-2 also showed less theta and alpha activity. Conversely, sigma and beta activity were more represented during SOREMP compared with the nocturnal REM period in patients with NT1. Conclusions: The analysis of the SOP supports the concept that SOREMP is a different state compared with both nocturnal REM sleep and non-REM sleep onset.

2017 - Stereotyped episodes of aphasia and immobility: how cataplexy mimics stroke in an elderly patient [Articolo su rivista]
Antelmi, E.; Pizza, F.; Vandi, S.; Plazzi, G.


2017 - The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder [Articolo su rivista]
Gan-Or, Ziv; Montplaisir Jacques, Y; Ross Jay, P; Poirier, Judes; Warby Simon, C; Arnulf, Isabelle; Strong, Stephanie; Dauvilliers, Yves; Leblond Claire, S; Hu Michele, T M; Högl, Birgit; Stefani, Ambra; Monaca Christelle, Charley; De Cock Valérie, Cochen; Boivin, Michel; Ferini-Strambi, Luigi; Plazzi, Giuseppe; Antelmi, Elena; Young, Peter; Heidbreder, Anna; Barber Thomas, R; Evetts Samuel, G; Rolinski, Michal; Dion Patrick, A; Desautels, Alex; Gagnon, Jean-François; Dupré, Nicolas; Postuma Ronald, B; Rouleau Guy, A

The present study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n&nbsp;= 480) and in controls (n&nbsp;= 823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR&nbsp;= 1.11, 95% CI: 0.88-1.40, p&nbsp;= 0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p&nbsp;= 1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.

2017 - The spectrum of REM sleep-related episodes in children with type 1 narcolepsy [Articolo su rivista]
Antelmi, Elena; Pizza, Fabio; Vandi, Stefano; Neccia, Giulia; Ferri, Raffaele; Bruni, Oliviero; Filardi, Marco; Cantalupo, Gaetano; Liguori, Rocco; Plazzi, Giuseppe

Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as 'classically-defined' and 'pantomime-like' REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having 'classically-defined' REM sleep behaviour disorder episodes and seven having 'pantomime-like' REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i.e. status cataplecticus) and more complaints of disrupted nocturnal sleep and of excessive daytime sleepiness. The neurophysiological hallmark of this severe motor dyscontrol during REM sleep was a decreased atonia index. The present study reports for the first time the occurrence of a severe and peculiar motor disorder during REM sleep in paediatric type 1 narcolepsy and confirms the presence of a severe motor dyscontrol in these patients, emerging not only from wakefulness (i.e. status cataplecticus), but also from sleep (i.e. complex behaviours during REM sleep). This is probably related to the acute imbalance of the hypocretinergic system, which physiologically acts by promoting movements during wakefulness and suppressing them during sleep.

2017 - Ultra-high-performance liquid chromatography tandem mass spectrometry determination of GHB, GHB-glucuronide in plasma and cerebrospinal fluid of narcoleptic patients under sodium oxybate treatment [Articolo su rivista]
Tittarelli, Roberta; Pichini, Simona; Pedersen, Daniel S.; Pacifici, Roberta; Moresco, Monica; Pizza, Fabio; Busardò, Francesco Paolo; Plazzi, Giuseppe

Sodium oxybate (Xyrem®), the sodium salt of γ- hydroxybutyric acid (GHB), is a first-line treatment of the symptoms induced by type 1 narcolepsy (NT1) and it is highly effective in improving sleep architecture, decreasing excessive daytime sleepiness and the frequency of cataplexy attacks. Using an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) validated method, GHB was determined together with its glucuronide (GHB-gluc), in plasma and cerebrospinal fluid (CSF) samples of NT1 patients under sodium oxybate treatment. To characterize the plasma pharmacokinetics of GHB, three subjects with NT1 were administered at time 0 and 4&nbsp;h with 1.25, 1.5 and 3.55&nbsp;g Xyrem®, respectively and had their blood samples collected at 7 time points throughout an 8-h session. CSF specimens, collected for orexin A measurement from the same three subjects 6&nbsp;h after their second administration, were also tested. The results obtained suggested that GHB plasma values increased disproportionally with the rising doses, (Cmax0–4: 12.53, 32.95 and 69.62&nbsp;μg/mL; Cmax4–8: 44.93, 75.03 and 111.93&nbsp;μg/mL for total Xyrem® dose of 2.5, 3 and 7&nbsp;g respectively) indicating non-linear dose-response. GHB-Gluc was present only in traces in all plasma samples from treated patients, not changing with increasing Xyrem® doses. GHB values of 5.62, 6.10 and 17.74&nbsp;μg/mL for 2, 3 and 7&nbsp;g Xyrem® were found in CSF with a significant difference from control values. GHB-Gluc was found in negligible concentrations with no differences to those of control individuals. In conclusion this simple and fast UHPLC–MS/MS method proved useful for pharmacokinetic studies and therapeutic drug monitoring of GHB in narcoleptic patients treated with sodium oxybate.

2016 - A pragmatic approach to test the reliability of a classification of permanent impairment due to narcolepsy [Abstract in Rivista]
Govi, A; Gnucci, V; Vignatelli, L; Zenesini, C; Ventrucci, C; Pizza, F; Plazzi, G; Ingravallo, F

2016 - A pragmatic approach to test the reliaility af permanent impairment classification [Relazione in Atti di Convegno]
Govi, A.; Valentina, Gnucci; Vignatelli, L.; Corrado, Zenesini; Pizza, F.; Plazzi, G.; Ingravallo, F.

2016 - Age-related differences in sleep-dependent consolidation of motor skills in patients with narcolepsy type 1 [Articolo su rivista]
Mazzetti, M.; Bellucci, C.; Cipolli, C.; Pizza, F.; Russo, P. M.; Tuozzi, G.; Vandi, S.; Plazzi, G.

Objective The influence of post-training sleep on the consolidation process of procedural (ie, visual and motor) knowledge has shown to be less effective in patients with chronic sleep disorders compared with healthy subjects. To ascertain whether the influence of the altered architecture of sleep in patients with narcolepsy type 1 (ie, with cataplexy: NT1) also varies with age, we compared the performance values of 16 children (aged from nine to 14 years) and 16 adults (aged from 24 to 51 years) on finger tapping task (FTT) after daytime and nighttime periods of sleep in the 24 hours following training. Methods All patients, who were drug-free and underwent continuous polysomnographic recordings, could take one or more naps after the training session (at 10 a.m.) until one hour before the first retrieval session (at 6 p.m.) and had an undisturbed period of nighttime sleep from about 10 p.m. to two hours before the second retrieval session (again at 10 a.m.). Results The pattern of sleep-dependent consolidation was significantly different in the two groups of patients: while performance accuracy was higher in adults compared with children at each session, performance speed improved after daytime sleep in children and after nighttime sleep in adults. The improvement in performance speed, although not related with any sleep parameters in both groups, was positively correlated with the daytime and nighttime total sleep time (TST) in children with greater consolidation gain. Conclusion The interaction between time of day and age in the time course of consolidation of new motor skills discloses a different role of daytime sleep (active in children, simply protective from interferences in adults) in NT1 patients and suggests a flexible use of napping in the educational context.

2016 - Attention network test reveals alerting network impairment in type 1 narcolepsy [Abstract in Atti di Convegno]
Filardi, Marco; Pizza, Fabio; Tonetti, Lorenzo; Plazzi, Giuseppe; Natale, Vincenzo

2016 - Cardiovascular autonomic dysfunctions and sleep disorders [Articolo su rivista]
Calandra-Buonaura, G.; Provini, F.; Guaraldi, P.; Plazzi, G.; Cortelli, P.

Animal and human studies have shown that disorders of the autonomic nervous system may influence sleep physiology. Conversely, sleep disorders may be associated with autonomic dysfunctions. The current review describes the clinical presentation, supposed pathogenetic mechanisms and the diagnostic and prognostic implications of impaired cardiovascular autonomic control in sleep disorders. This dysfunction may result from a common pathogenetic mechanism affecting both autonomic cardiovascular control and sleep, as in fatal familial insomnia, or it may be mainly caused by the sleep disorder, as observed in obstructive sleep apnoea. For other sleep disorders, like primary insomnia, restless legs syndrome, narcolepsy type 1 and rapid eye movement sleep behaviour disorder, the causal link with the autonomic dysfunction and its possible impact on health remains unsettled. Given its clinical implications, most of the data available suggest that a systematic assessment of the association between sleep disorders and impaired autonomic control of the cardiovascular system is warranted. Understanding the mechanism of this association may also yield insights into the interaction between the autonomic nervous system and sleep.

2016 - Circadian Rest-Activity Rhythm in Pediatric Type 1 Narcolepsy [Articolo su rivista]
Filardi, Marco; Pizza, Fabio; Bruni, Oliviero; Natale, Vincenzo; Plazzi, Giuseppe

Pediatric type 1 narcolepsy is often challenging to diagnose and remains largely undiagnosed. Excessive daytime sleepiness, disrupted nocturnal sleep, and a peculiar phenotype of cataplexy are the prominent features. The knowledge available about the regulation of circadian rhythms in affected children is scarce. This study compared circadian rest-activity rhythm and actigraphic estimated sleep measures of children with type 1 narcolepsy versus healthy controls.

2016 - Circadian sleep propensity and alcohol interaction at the wheel [Articolo su rivista]
Garbarino, Sergio; Nobili, Lino; Philip, Pierre; Plazzi, Giuseppe; Campus, Claudio; Morrone, Elisa; De Carli, Fabrizio

Study Objectives: The study was aimed at estimating the effect of alcohol consumption, time of day, and their interaction on traffic crashes in a real regional context. Methods: Blood alcohol concentration (BAC) data were collected from drivers involved in traffic accidents during one year in an Italian region and in a control group of drivers over the same road network. Mean circadian sleep propensity was estimated from a previous study as function of time of day. Accident risk was analyzed by logistic regression as function of BAC and circadian sleep propensity. Results: BAC values greater than zero were found in 72.0% of the drivers involved in crashes and in 40.4% of the controls. Among the former 23.6% of the drivers exceeded the BAC legal threshold of 0.05 g/dL, while illegal values were found in 10.4% of the controls. The relative risk showed a significant increase with both BAC and circadian sleep propensity (as estimated from time of day) and their interaction was significant. Conclusions: Due to the significant interaction, even low BAC levels strongly increased accident risk when associated with high sleep propensity.

2016 - Decreased sleep stage transition pattern complexity in narcolepsy type 1 [Articolo su rivista]
Ferri, Raffaele; Pizza, Fabio; Vandi, Stefano; Iloti, Martina; Plazzi, Giuseppe

Objective To analyze the complexity of the nocturnal sleep stage sequence in central disorders of hypersomnolence (CDH), with the hypothesis that narcolepsy type 1 (NT1) might exhibit distinctive sleep stage sequence organization and complexity. Methods Seventy-nine NT1 patients, 22 narcolepsy type 2 (NT2), 22 idiopathic hypersomnia (IH), and 52 patients with subjective hypersomnolence (sHS) were recruited and their nocturnal sleep was polysomnographically recorded and scored. Group between-stage transition probability matrices were obtained and compared. Results Patients with NT1 differed significantly from all the other patient groups, the latter, in turn, were not different between each other. The individual probability of the R-to-N2 transition was found to be the parameter showing the difference of highest significance between the groups (lowest in NT1) and classified patients with or without NT1 with an accuracy of 78.9% (sensitivity 78.5% and specificity 79.2%), by applying a cut-off value of 0.15. Conclusions The main result of this study is that the structure of the sleep stage transition pattern of hypocretin-deficient NT1 patients is significantly different from that of other forms of CDH and sHS, with normal hypocretin levels. Significance The lower probability of R-to-N2 transition occurrence in NT1 appears to be a reliable polysomnographic feature with potential application at the individual level, for supportive diagnostic purposes.

2016 - Dissociated rapid eye movement sleep dream experiences in type 1 narcolepsy: A case report [Articolo su rivista]
Bellucci, Claudia; Vandi, Stefano; Iloti, Martina; Pizza, Fabio; Russo, Paolo Maria; Tuozzi, Giovanni; Cipolli, C.; Plazzi, Giuseppe


2016 - From state dissociation to status dissociatus [Articolo su rivista]
Antelmi, Elena; Ferri, Raffaele; Iranzo, Alex; Arnulf, Isabelle; Dauvilliers, Yves; Bhatia Kailash, P; Liguori, Rocco; Schenck Carlos, H; Plazzi, Giuseppe

The states of being are conventionally defined by the simultaneous occurrence of behavioral, neurophysiological and autonomic descriptors. State dissociation disorders are due to the intrusion of features typical of a different state into an ongoing state. Disorders related to these conditions are classified according to the ongoing main state and comprise: 1) Dissociation from prevailing wakefulness as seen in hypnagogic or hypnopompic hallucinations, automatic behaviors, sleep drunkenness, cataplexy and sleep paralysis 2) Dissociation from rapid eye movement (REM) sleep as seen in REM sleep behavior disorder and lucid dreaming and 3) Dissociation from NREM sleep as seen in the disorders of arousal. The extreme expression of states dissociation is characterized by the asynchronous occurrence of the various components of the different states that prevents the recognition of any state of being. This condition has been named status dissociatus. According to the underlying disorders/diseases and to their severity, among status dissociatus we may recognize disorders in which such an extreme dissociation occurs only at night time or intermittently (i.e., autoimmune encephalopathies, narcolepsy type 1 and IgLON5 parasomnia), and others in which it occurs nearly continuously with complete loss of any conventionally defined state of being, and of the circadian pattern (agrypnia excitata). Here, we render a comprehensive review of all diseases/disorders associated with state dissociation and status dissociatus and propose a critical classification of this complex scenario.

2016 - Growing Up with Type 1 narcolepsy: Its anthropometric and endocrine features [Articolo su rivista]
Ponziani, Virginia; Gennari, Monia; Pizza, Fabio; Balsamo, Antonio; Bernardi, Filippo; Plazzi, Giuseppe

Study Objectives: To evaluate the effect of type 1 narcolepsy (NT1) on anthropometric and endocrine features in childhood/adolescence, focusing on patterns and correlates of weight, pubertal development, and growth in treated and untreated patients. Methods: We collected anthropometric (height, weight, body mass index (BMI) z-scores), pubertal, metabolic, and endocrine data from 72 NT1 patients at diagnosis and all available premorbid anthropometric parameters of patients from their pediatric files (n = 30). New measurements at 1-y reassessment in patients undergoing different treatments were compared with baseline data. Results: We detected a high prevalence of overweight (29.2%), obesity (25%), metabolic syndrome (18.8%), and precocious puberty (16.1%), but no signs of linear growth alterations at diagnosis. According to anthropometric records, weight gain started soon after NT1 onset. At 1-y follow-up reassessment, sodium oxybate treatment was associated with a significant BMI z-score reduction (-1.29 ± 0.30, p &lt; 0.0005) after adjusting for baseline age, sex, sleepiness, and BMI. Conclusions: NT1 onset in children/adolescents is associated with rapid weight gain up to overweight/obesity and precocious puberty without affecting growth. In our study, sodium oxybate treatment resulted in a significant weight reduction in NT1 overweight/obese patients at 1-y follow-up.

2016 - High anti-streptolysin-O titres and blood-brain barrier damage in narcolepsy type 1 in the first year after symptoms onset [Abstract in Rivista]
Moresco, M; Liguori, R; Avoni, P; Mignot, E; Lin, L; Plazzi, G; Pizza, F

2016 - Immune characterization in Narcolepsy Type 1 [Abstract in Rivista]
Moresco, M; Ocadlikova, D; Pizza, F; Lecciso, M; Curti, A; Plazzi, G

2016 - Intermittent head drops: the differential spectrum [Articolo su rivista]
Antelmi, E.; Plazzi, G.; Erro, R.; Tinuper, P.; Balint, B.; Liguori, R.; Bhatia, K. P.

Intermittent Head Drops are episodic head flexion movements that can occur in a number of conditions. Typically, the term has mainly been related to epileptic episodes, but the spectrum of clinical conditions associated with this feature is wide-ranging even if never discussed in detail. By searching the electronic database, we may find that apart from the epileptic conditions, Intermittent Head Drops have been in fact reported in the setting of movement disorders, sleep disorders and even internal medicine disorders, such as Sandifer syndrome. We render an in-depth description of this characteristic phenomenon in different diseases, describing the clinical clues and neurophysiological patterns that may help the clinician to distinguish between the different settings of occurrence.

2016 - Medicolegal Aspects of Disability in Narcolepsy [Capitolo/Saggio]
Ingravallo, Francesca; Plazzi, Giuseppe

Narcolepsy is a severe, chronic, disabling disease affecting almost all personal and social activities. Sleep disorder specialists deal with the disabling burden of narcolepsy since their first approach to the patient. The disease continues to be a burden throughout the patient’s life as pharmacological and behavioral treatments only seldom control the variety of symptoms. Empirical data showed that from one fourth to half of people with narcolepsy are forced to modify or leave a job due to the disease, which may also cause higher absenteeism due to disability and accidents, as well as being more likely subjected to unemployment and early retirement with high social and economic costs. Excessive daytime sleepiness seems to be the main symptom associated with work disability, but cataplexy may be even more disabling in cases with many cataplectic attacks. Since people with narcolepsy experience a wide range of occupational problems, both clinicians and researchers are interested in how to help their patients to hold down a job, return to work, and, if necessary, receive benefits for work disability. This chapter considers the medicolegal aspects of work disability in narcolepsy, summarizing essential issues clinicians and researchers have to address in providing medical information to assist disability determination in people with narcolepsy.

2016 - Narcolepsy features in young patients [Articolo su rivista]
Govi, Annamaria; Antelmi, Elena; Pizza, Fabio; Ingravallo, Francesca; Plazzi, Giuseppe

Narcolepsy is a lifelong central hypersomnia characterized by excessive daytime sleepiness, cataplex y, sleep paralysis, hypnagogic hallucinations, and disrupted noc- turnal sleep. Behavioral and psychiatric comorbidities are often associated clinical features. It is divided into t wo subt ypes, narcolepsy t ype -1, and narcolepsy t ype -2, depending on the presence of cataplex y and the cerebrospinal fluid hypocretin-1 l evels. An autoimmune process, along with environmental factors, has been hypothesized to cause the disease. Among children and adolescents, incidence in Europe falls bet ween 0.14 and 0.3 in 100,000, with a reported increase in the incidence af ter the 2009 H1N1 pandemic influence and vaccination. Currently, specific pediatric diagnostic criteria and cut-off instrumental values are lacking. Clinical presentation of the disease may differ between children and adults, and misdiagnoses or diagnostic delays are still an issue. The treatment is based on behavioral and pharmacological therapy, but drugs in children a re prescribed off-l abel. Overall, pathogenic mechanism of narcolepsy and data on drug efficac y in chil dren are still li mited: more research is needed to develop new drugs and to reach approval of current treatments in the pediatric population.

2016 - Parkinsonian tremor persisting during cataplexy [Articolo su rivista]
Antelmi, E; Vandi, S.; Pizza, F.; Liguori, R.; Plazzi, G.


2016 - Pharmacogenetics and Treatment Response in Narcolepsy Type 1: Relevance of the Polymorphisms of the Drug Transporter Gene ABCB1 [Articolo su rivista]
Moresco, Monica; Riccardi, LAURA NATALIA; Pizza, Fabio; Zenesini, Corrado; Caporali, Leonardo; Plazzi, Giuseppe; Pelotti, Susi

OBJECTIVE: Narcolepsy type 1 (NT1) is a chronic hypersomnia clinically characterized by daytime sleepiness and cataplexy. Narcolepsy type 1 treatments target individual symptoms: wake-promoting agents (eg, modafinil) are effective for sleepiness, antidepressants (eg, venlafaxine) on cataplexy, whereas sodium oxybate on both. Narcolepsy type 1 patients variably respond to modafinil and venlafaxine independently of individual clinical features.Given the potential influence of drug transmembrane transport (glycoprotein-P) on drug response, we explored the relation between genetic polymorphisms in the ABCB1 gene and clinical response to modafinil/venlafaxine in NT1. METHODS: Individual drug response and genotypes were assessed in 107 NT1 patients (males/females, 64/43; mean age, 38 ± 21 years) treated with modafinil and/or venlafaxine at stable doses for at least 3 months. Minisequencing was performed to detect single-nucleotide polymorphisms in ABCB1. Patients with different responses to treatment were contrasted by Fisher exact test and multivariate analysis. RESULTS: The ABCB1 diplotype was significantly associated with clinical response to modafinil, with the CGC-TTT (1236/2677/3435) being more frequent in the modafinil responder versus nonresponder group (P = 0.013). Conversely, no significant associations with clinical response to venlafaxine were found. CONCLUSIONS: The ABCB1 variants modulate therapeutic response to modafinil and may partly explain pharmacoresistance in NT1 patients.

2016 - Psychosocial profile and quality of life in children with type 1 narcolepsy: A case-control study [Articolo su rivista]
Rocca Francesca, Letizia; Finotti, Elena; Pizza, Fabio; Ingravallo, Francesca; Gatta, Michela; Bruni, Oliviero; Plazzi, Giuseppe

Study Objectives: To investigate behavioral aspects and quality of life in children and adolescents with type 1 narcolepsy (NT1). Methods: We performed a case-control study comparing 29 patients with NT1 versus sex- and age-matched patients with idiopathic epilepsy (n = 39) and healthy controls (n = 39). Behavior and quality of life were evaluated by self-administered questionnaires (Child Behavior Checklist, Pediatric Quality of Life Inventory). Patient groups were contrasted and scale results were correlated with clinical and polysomnographic parameters, and cerebrospinal fluid hypocretin-1 levels. Results: Young patients with NT1 showed increased internalizing problems associated with aggressive behavior. Emotional profile in patients with NT1 positively correlated with age at onset, diagnostic delay, and subjective sleepiness, whereas treatment and disease duration were associated with fewer behavioral problems (attention problems, aggressive behavior, and attention deficit/hyperactivity disorder). Psychosocial health domains of pediatric NT1 were worse than in healthy controls, whereas the physical health domains were comparable. Conclusions: Young NT1 patients show a discrete pattern of altered behavioral, thought, and mood profile in comparison with healthy controls and with idiopathic epilepsy patients thus suggesting a direct link with sleepiness. Further studies investigating behavior in patients with idiopathic hypersomnia or type 2 narcolepsy are needed to disentangle the role of REM sleep dysfunction and hypocretin deficiency in psychiatric disorders. Symptoms of withdrawal, depression, somatic complaints, thought problems, and aggressiveness were common, NT1 children perceived lower school competencies than healthy children, and their parents also reported worse psychosocial health.Our data suggest that early effective treatment and disease self-awareness should be promoted in NT1 children for their positive effect on behavior and psychosocial health.

2016 - The European Narcolepsy Network (EU-NN) database [Articolo su rivista]
Khatami, Ramin; Luca, Gianina; Baumann, Christian R; Bassetti, Claudio L; Bruni, Oliviero; Canellas, Francesca; Dauvilliers, Yves; Del Rio Villegas, Rafael; Feketeova, Eva; Ferri, Raffaele; Geisler, Peter; Högl, Birgit; Jennum, Poul; Kornum, Birgitte R; Lecendreux, Michel; Martins da Silva, Antonio; Mathis, Johannes; Mayer, Geert; Paiva, Teresa; Partinen, Markku; Peraita Adrados, Rosa; Plazzi, Giuseppe; Santamaria, Joan; Sonka, Karel; Riha, Renata; Tafti, Mehdi; Wierzbicka, Aleksandra; Young, Peter; Lammers, Gert Jan; Overeem, Sebastiaan

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

2016 - World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG) [Articolo su rivista]
Ferri, R; Fulda, S.; Manconi, M.; Allen, R. P.; Zucconi, M.; Ferini-Strambi, L.; Bruni, O.; Chokroverty, S.; Frauscher, B.; Garcia-Borreguero, D.; Hirshkowitz, M.; Högl, B.; Inoue, Y.; Jahangir, A.; Marcus, C. L.; Picchietti, D. L.; Plazzi, G.; Winkelman, J. W.; Zak, R. S.

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5–10 s long or bilateral LM 0.5–15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval &lt;10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM &gt; 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

2015 - Actigraphic assessment of sleep/wake behavior in central disorders of hypersomnolence [Articolo su rivista]
M., Filardi; Pizza, Fabio; Martoni, Monica; Vandi, Stefano; Plazzi, Giuseppe; Natale, Vincenzo

To evaluate the reliability of actigraphy to distinguish the features of estimated daytime and nighttime sleep between patients with central disorders of hypersomnolence and healthy controls.Thirty-nine drug-naïve patients with Narcolepsy Type 1, twenty-four drug-naïve patients with Idiopathic Hypersomnia, and thirty age- and sex- matched healthy controls underwent seven days of actigraphic and self-report monitoring of sleep/wake behavior. The following variables were examined: estimated time in bed (eTIB), estimated total sleep time, estimated sleep latency (eSOL), estimated sleep efficiency, estimated wake after sleep onset, number of estimated awakenings (eAwk), number of estimated awakenings longer than 5 minutes, estimated sleep motor activity (eSMA), number of estimated naps, mean duration of the longest estimated nap (eNapD), and daytime motor activity.All actigraphic parameters significantly differentiated the three groups, except eTIB and eSOL. A discriminant score computed combining actigraphic parameters from nighttime (eSMA, eAwk) and daytime (eNapD) periods showed a wide area under the curve (0.935) and a good balance between positive (95%) and negative predictive (87%) values in Narcolepsy Type 1 cases.Actigraphy provided a reliable objective measurement of sleep quality and daytime napping behavior able to distinguish central disorders of hypersomnolence and in particular Narcolepsy Type 1. The nycthemeral profile, combined with a careful clinical evaluation, may be an ecological information, useful to track disease course.

2015 - Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus [Articolo su rivista]
Saariaho, A. -H.; Vuorela, A.; Freitag, T. L.; Pizza, F.; Plazzi, G.; Partinen, M.; Vaarala, O.; Meri, S.

Following the mass vaccinations against pandemic influenza A/H1N1 virus in 2009, a sudden increase in juvenile onset narcolepsy with cataplexy (NC) was detected in several European countries where AS03-adjuvanted Pandemrix vaccine had been used. NC is a chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy. In human NC, the hypocretin-producing neurons in the hypothalamus or the hypocretin signaling pathway are destroyed by an autoimmune reaction. Both genetic (e.g. HLA-DQB1*0602) and environmental risk factors (e.g. Pandemrix) contribute to the disease development, but the underlying and the mediating immunological mechanisms are largely unknown. Influenza virus hemagglutinin is known to bind gangliosides, which serve as host cell virus receptors. Anti-ganglioside antibodies have previously been linked to various neurological disorders, like the Guillain-Barré syndrome which may develop after infection or vaccination. Because of these links we screened sera of NC patients and controls for IgG anti-ganglioside antibodies against 11 human brain gangliosides (GM1, GM2, GM3, GM4, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GQ1b) and a sulfatide by using a line blot assay. Samples from 173 children and adolescents were analyzed: 48 with Pandemrix-associated NC, 20 with NC without Pandemrix association, 57 Pandemrix-vaccinated and 48 unvaccinated healthy children. We found that patients with Pandemrix-associated NC had more frequently (14.6%) anti-GM3 antibodies than vaccinated healthy controls (3.5%) (P = 0.047). Anti-GM3 antibodies were significantly associated with HLA-DQB1*0602 (P = 0.016) both in vaccinated NC patients and controls. In general, anti-ganglioside antibodies were more frequent in vaccinated (18.1%) than in unvaccinated (7.3%) individuals (P = 0.035). Our data suggest that autoimmunity against GM3 is a feature of Pandemrix-associated NC and that autoantibodies against gangliosides were induced by Pandemrix vaccination.

2015 - Car Crashes and Central Disorders of Hypersomnolence: A French Study [Articolo su rivista]
Pizza, Fabio; I., Jaussent; R., Lopez; C., Pesenti; Plazzi, Giuseppe; X., Drouot; S., Leu Semenescu; S., Beziat; I., Arnulf; Y., Dauvilliers

Drowsiness compromises driving ability by reducing alertness and attentiveness, and delayed reaction times. Sleep-related car crashes account for a considerable proportion of accident at the wheel. Narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) are rare central disorders of hypersomnolence, the most severe causes of sleepiness thus being potential dangerous conditions for both personal and public safety with increasing scientific, social, and political attention. Our main objective was to assess the frequency of recent car crashes in a large cohort of patients affected with well-defined central disorders of hypersomnolence versus subjects from the general population.We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 527 patients and 781 healthy subjects. All participants included needed to have a driving license, information available on potential accident events during the last 5 years, and on potential confounders; thus analyses were performed on 282 cases (71 IH, 82 NT2, 129 NT1) and 470 healthy subjects.Patients reported more frequently than healthy subjects the occurrence of recent car crashes (in the previous five years), a risk that was confirmed in both treated and untreated subjects at study inclusion (Untreated, OR = 2.21 95\%CI = [1.30-3.76], Treated OR = 2.04 95\%CI = [1.26-3.30]), as well as in all disease categories, and was modulated by subjective sleepiness level (Epworth scale and naps). Conversely, the risk of car accidents of patients treated for at least 5 years was not different to healthy subjects (OR = 1.23 95\%CI = [0.56-2.69]). Main risk factors were analogous in patients and healthy subjects.Patients affected with central disorders of hypersomnolence had increased risk of recent car crashes compared to subjects from the general population, a finding potentially reversed by long-term treatment.

2015 - Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset [Articolo su rivista]
Kornum, B. R.; Pizza, F.; Knudsen, S.; Plazzi, G.; Jennum, P.; Mignot, E.

Type 1 narcolepsy is caused by a loss of hypocretin (orexin) signaling in the brain. Genetic data suggests the disorder is caused by an autoimmune attack on hypocretin producing neurons in hypothalamus. This hypothesis has however not yet been confirmed by consistent findings of autoreactive antibodies or T-cells in patient samples. One explanation for these negative results may be that the autoimmune process is no longer active when patients present to the clinic. With increasing awareness in recent years, more and more patients have been diagnosed closer and closer to disease onset. In this study, we tested whether an active immune process in the brain could be detected in these patients, as reflected by increased cytokine levels in the cerebrospinal fluid (CSF). Using multiplex analysis, we measured the levels of 51 cytokines and chemokines in the CSF of 40 type 1 narcolepsy patients having varying disease duration. For comparison, we used samples from 9 healthy controls and 9 patients with other central hypersomnia. Cytokine levels did not differ significantly between controls and patients, even in 5 patients with disease onset less than a month prior to CSF sampling.

2015 - Erratum: HLA-DPB1 and HLA class i confer risk of and protection from narcolepsy (American Journal of Human Genetics (2015) 96 (136-146)) [Articolo su rivista]
Ollila, H. M.; Ravel, J. -M.; Han, F.; Faraco, J.; Lin, L.; Zheng, X.; Plazzi, G.; Dauvilliers, Y.; Pizza, F.; Hong, S. -C.; Jennum, P.; Knudsen, S.; Kornum, B. R.; Dong, X. S.; Yan, H.; Hong, H.; Coquillard, C.; Mahlios, J.; Jolanki, O.; Einen, M.; Arnulf, I.; Hogl, B.; Frauscher, B.; Crowe, C.; Partinen, M.; Huang, Y. S.; Bourgin, P.; Vaarala, O.; Desautels, A.; Montplaisir, J.; Mack, S. J.; Mindrinos, M.; Fernandez-Vina, M.; Mignot, E.

2015 - HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy [Articolo su rivista]
Ollila, H. M.; Ravel, J.; Han, F.; Faraco, J.; Lin, L.; Zheng, X.; Plazzi, G.; Dauvilliers, Y.; Pizza, F.; Hong, S.; Jennum, P.; Knudsen, S.; Kornum, B. R.; Dong, X. S.; Yan, H.; Hong, H.; Coquillard, C.; Mahlios, J.; Jolanki, O.; Einen, M.; Lavault, S.; Högl, B.; Frauscher, B.; Crowe, C.; Partinen, M.; Huang, Y. S.; Bourgin, P.; Vaarala, O.; Désautels, A.; Montplaisir, J.; Mack, S. J.; Mindrinos, M.; Fernandez-Vina, M.; Mignot, E.

Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class&nbsp;II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01&nbsp;× 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07&nbsp;× 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71&nbsp;× 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99&nbsp;× 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11&nbsp;× 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92&nbsp;× 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14&nbsp;× 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09&nbsp;× 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

2015 - Incidence of sudden unexpected death in nocturnal frontal lobe epilepsy: a cohort study [Articolo su rivista]
Mostacci, B.; Bisulli, F.; Vignatelli, L.; Licchetta, L.; Vito, L. D.; Rinaldi, C.; Trippi, I.; Ferri, L.; Plazzi, G.; Provini, F.; Tinuper, P.

Most cases of sudden unexpected death in epilepsy (SUDEP) follow a seizure, and most deaths occur while people are in bed, presumably sleeping. Nocturnal seizures are reported to be a risk factor for SUDEP. People with nocturnal frontal lobe epilepsy (NFLE) have seizures predominantly or exclusively during sleep, often many times per night. The present study aimed to assess whether NFLE represents a high-risk condition for SUDEP.The present study retrospectively assessed the incidence of SUDEP in a cohort reconstructed from a dedicated database of consecutive patients referred to the Epilepsy and Sleep Centres of the Institute of Neurological Sciences of Bologna from 1980 to 2012 with: (1) a diagnosis of NFLE, (2) at least 90% of seizures during sleep, and (3) at least one-year of follow-up.One hundred and three people were included. The median time from seizure onset to last observation was 26 years, equal to a follow-up of 2789 person-years. One person died of SUDEP during the follow-up period. The incidence rate of SUDEP was 0.36 per 1000 person-years (95% CI 0.01 to 2.0).The incidence of SUDEP in the participant population was not higher than the rates previously reported in prevalent epilepsy populations (0.4 to 2.3 per 1000 person-years). The low prevalence of SUDEP might reflect the low occurrence of generalised tonic-clonic seizures in people with NFLE.

2015 - Narcolepsy during Childhood: An Update [Articolo su rivista]
F. L., Rocca; Pizza, Fabio; E., Ricci; Plazzi, Giuseppe

Narcolepsy type 1 (NT1) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and fragmented nocturnal sleep usually arising in adolescence or young adulthood. Recently, the childhood NT1 diagnoses have increased for improved disease awareness and for several cases occurring after the H1N1 pandemic influenza or vaccination. As in adults, the occurrence of NT1 in individuals with a genetic predisposition of the immune system (e.g., human leukocyte antigen, HLA-DQB1*0602) together with the role of environmental triggers (e.g., H1N1 influenza virus, streptococcus β hemolyticus) further supports the autoimmune pathogenesis. Children with NT1 close to disease onset show a peculiar cataplexy phenotype characterized by persistent hypotonia with prominent facial involvement (cataplectic facies) and by a complex mosaic of hyperkinetic movement abnormalities that increase during emotional stimulation. This phenotype progressively vanishes along the disease course leading to the typical picture of cataplexy (i.e., muscle weakness exclusively evoked by strong emotions). This possibly explains in part the misdiagnoses and diagnostic delay. Childhood NT1 also shows behavioral abnormalities and psychiatric disorders, encompassing depressive feelings, hyperactive/aggressive behavior, up to psychotic features. The association with obesity and precocious puberty strikingly suggests that NT1 arising in prepubertal children may reflect a wide hypothalamic derangement secondary to hypocretin neuronal loss. The complexity of the childhood NT1 phenotype claims a multidisciplinary assessment and management, taking behavioral and endocrinological features into account. NT1 indeed is a lifelong disorder with a devastating impact on quality of life, especially when arising across developmental age, and targeted school programs, medicolegal and psychological supports are essential for patients care. Controlled studies are mandatory to assess safety and efficacy of the current symptomatic off-label medications on which also relies the treatment for children with NT1, and hopefully future pathogenetic evidences will pave the way to better disease prevention and therapies to modify the disease course.

2015 - Narcolepsy Type 1 and Idiopathic Generalized Epilepsy: Diagnostic and Therapeutic Challenges in Dual Cases [Articolo su rivista]
Baiardi, Simone; Vandi, Stefano; Pizza, Fabio; Alvisi, Lara; Toscani, Lucia; Zambrelli, Elena; Tinuper, Paolo; Mayer, Geert; Plazzi, Giuseppe

The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments.

2015 - Nocturnal Sleep Dynamics Identify Narcolepsy Type 1 [Articolo su rivista]
Pizza, F.; Vandi, S.; Iloti, M.; Franceschini, C.; Liguori, R.; Mignot, E.; Plazzi, G.

To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory.One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52).None.Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1.Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients showed the highest number of awakenings, sleep stage transitions, and more time spent in N1 sleep, as well as most SOREMPs at daytime PSG and at Multiple Sleep Latency Tests (MSLTs) than all other groups. ROC curve analysis showed that nocturnal SOREMP (area under the curve of 0.724 ± 0.041, P &lt; 0.0001), percent of total sleep time spent in N1 (0.896 ± 0.023, P &lt; 0.0001), and the wakefulness-sleep transition index (0.796 ± 0.034, P &lt; 0.0001) had a good sensitivity and specificity profile to identify NT1 sleep, especially when used in combination (0.903 ± 0.023, P &lt; 0.0001), similarly to SOREMP number at continuous daytime PSG (0.899 ± 0.026, P &lt; 0.0001) and at MSLT (0.956 ± 0.015, P &lt; 0.0001).Sleep macrostructure (i.e. SOREMP, N1 timing) including stage transitions reliably identifies NT1 among central disorders of hypersomnolence.

2015 - Response to the letter "New avenues to prevent sudden unexpected death in nocturnal frontal lobe epilepsy: follow the route established by omega-3 polyunsaturated fatty acids" [Articolo su rivista]
Mostacci, B.; Bisulli, F.; Vignatelli, L.; Licchetta, L.; Vito, L. D.; Rinaldi, C.; Trippi, I.; Ferri, L.; Plazzi, G.; Provini, F.; Tinuper, P.

2015 - Response to the letter to the editor from Dr. Kawada, "Characteristics of patients with hypersomnia by actigraphy" [Articolo su rivista]
Filardi, M.; Pizza, Fabio; Martoni, Monica; Vandi, Stefano; Plazzi, Giuseppe; Natale, Vincenzo


2015 - Schizophrenia-Like Symptoms in Narcolepsy Type 1: Shared and Distinctive Clinical Characteristics [Articolo su rivista]
Plazzi, Giuseppe; Fabbri, C.; Pizza, Fabio; Serretti, Alessandro

The occurrence of psychotic symptoms in narcolepsy type 1 (NT1) has been reported as responsible for delayed diagnosis due to the misdiagnosis of schizophrenia. This study aimed to identify shared and distinctive clinical characteristics between NT1 and schizophrenia, with the focus on psychotic symptoms.

2015 - The Brain Correlates of Laugh and Cataplexy in Childhood Narcolepsy [Articolo su rivista]
Meletti, Stefano; Vaudano, Anna Elisabetta; Pizza, Fabio; Ruggieri, Andrea; Vandi, Stefano; Teggi, Alberto; Franceschini, Christian; Benuzzi, Francesca; Nichelli, Paolo Frigio; Plazzi, Giuseppe

The brain suprapontine mechanisms associated with human cataplexy have not been clarified. Animal data suggest that the amygdala and the ventromedial prefrontal cortex are key regions in promoting emotion-induced cataplectic attacks. Twenty-one drug-naive children/adolescent (13 males, mean age 11 years) with recent onset of narcolepsy type 1 (NT1) were studied with fMRI while viewing funny videos using a "naturalistic" paradigm. fMRI data were acquired synchronously with EEG, mylohyoid muscle activity, and the video of the patient's face. Whole-brain hemodynamic correlates of (1) a sign of fun and amusement (laughter) and of (2) cataplexy were analyzed and compared. Correlations analyses between these contrasts and disease-related variables and behavioral findings were performed.

2014 - A case of REM sleep behavior disorder, narcolepsy-cataplexy, parkinsonism and rheumatoid arthritis [Articolo su rivista]
F. I. I., Cosentino; A., Distefano; Plazzi, Giuseppe; C. H., Schenck; R., Ferri

A patient is reported in whom signs and symptoms of REM sleep behavior disorder (RBD) and narcolepsy have been associated for almost two decades with a late development of parkinsonism and rheumatoid arthritis. A 78-year-old male patient in whom RBD was first diagnosed was followed-up by clinical examination, videopolysomnography, multiple sleep latency test, cerebral magnetic resonance imaging, and dopamine transporter imaging by single-photon emission computerized tomography. The patient was found to present for almost two decades, in addition to RBD, also narcolepsy. Moreover, a late development of parkinsonism and the occurrence of rheumatoid arthritis were detected and clinically and instrumentally characterized. Patients predisposed to RBD and later parkinsonism might be susceptible to a variety of triggers that, in our patient, might have been represented by a possible latent autoimmune process leading to the development of narcolepsy with cataplexy and rheumatoid arthritis, later.

2014 - An International Consensus on the Forensic Assessment of Sleep-Related Violence and Sexual Behavior in Sleep: If Not Now, When? [Articolo su rivista]
Ingravallo, Francesca; Poli, Francesca; Gilmore, Emma V.; Pizza, Fabio; Vignatelli, Luca; Schenck, Carlos H.; Plazzi, Giuseppe

2014 - Cataplectic attacks during rapid eye movement sleep behavior disorder episodes in a narcoleptic patient [Articolo su rivista]
Baiardi, S.; Pizza, F.; Vandi, S.; Franceschini, C.; Vigo, A.; Cipolli, C.; Tuozzi, G.; Liguori, R.; Plazzi, G.

2014 - Challenges in diagnosing narcolepsy without cataplexy: a consensus statement [Articolo su rivista]
Baumann, C. R.; Mignot, E.; Lammers, G. J.; Overeem, S.; Arnulf, I.; Rye, D.; Dauvilliers, Y.; Honda, M.; Owens, J. A.; Plazzi, G.; Scammell, T. E.

Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy.A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy.To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10\% to 30\% of narcolepsy without cataplexy patients.

2014 - Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases [Articolo su rivista]
Pizza, F.; Peltola, H.; Sarkanen, T.; Moghadam, K. K.; Plazzi, G.; Partinen, M.

We aimed to compare post-Pandemrix vaccination (postvaccine) childhood narcolepsy with cataplexy (NC) vs. sporadic pre-H1N1 pandemic (pre-H1N1) cases.Clinical, anthropometric, polysomnographic, and cerebrospinal hypocretin 1 (hcrt-1) measurements were collected together with the video recordings of cataplexy in 27 Finnish patients with NC onset after H1N1 Pandemrix vaccination (mean age, 12±4 years; 52\% boys) and 42 Italian NC patients with NC onset before the H1N1 pandemic (mean age, 11±3 years; 48\% boys). All subjects carried the HLA-DQB1*0602 allele.Postvaccine subjects were older at NC onset (12±3 vs. 9±3 years; P=.008) and displayed a shorter mean sleep latency in multiple sleep latency tests (MSLT) (2.3±2.2 vs. 3.7±2.9 min; P=.026) compared to pre-H1N1 cases. Anthropometric, clinical (core NC symptoms), hcrt-1 deficiency, and polysomnographic data did not differ among groups, but higher disrupted nocturnal sleep was observed in postvaccine subjects. Comparison of cataplexy features at video assessment showed an overlapping picture with the exception for hyperkinetic movements which appeared to be more evident in pre-H1N1 subjects.The clinical picture of childhood NC was similar in postvaccine and pre-H1N1 children.

2014 - Comorbidities and special populations [Capitolo/Saggio]
Pizza, F.; Plazzi, G.; Dauvilliers, Y.


2014 - Corrigendum to "Rapid eye movement sleep behavior disorder: Devising controlled active treatment studies for symptomatic and neuroprotective therapy-a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group" [Sleep Med 14(8) (2013) 795-806] [Articolo su rivista]
Schenck, C. H.; Montplaisir, J. Y.; Frauscher, B.; Hogl, B.; Gagnon, J. -F.; Postuma, R.; Sonka, K.; Jennum, P.; Partinen, M.; Arnulf, I.; de Cock, V. C.; Dauvilliers, Y.; Luppi, P. -H.; Heidbreder, A.; Mayer, G.; Sixel-Doring, F.; Trenkwalder, C.; Unger, M.; Young, P.; Wing, Y. K.; Ferini-Strambi, L.; Ferri, R.; Plazzi, G.; Zucconi, M.; Inoue, Y.; Iranzo, A.; Santamaria, J.; Bassetti, C.; Moller, J. C.; Boeve, B. F.; Lai, Y. Y.; Pavlova, M.; Saper, C.; Schmidt, P.; Siegel, J. M.; Singer, C.; St Louis, E.; Videnovic, A.; Oertel, W.

2014 - Does autoreactivity have a role in narcolepsy? [Articolo su rivista]
Partinen, M.; Kornum, B. R.; Plazzi, G.; Jennum, P.; Julkunen, I.; Vaarala, O.


2014 - DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe [Articolo su rivista]
Tafti, M.; Hor, H.; Dauvilliers, Y.; Lammers, G. J.; Overeem, S.; Mayer, G.; Javidi, S.; Iranzo, A.; Santamaria, J.; Peraita-Adrados, R.; Vicario, J. L.; Arnulf, I.; Plazzi, G.; Bayard, S.; Poli, F.; Pizza, F.; Geisler, P.; Wierzbicka, A.; Bassetti, C. L.; Mathis, J.; Lecendreux, M.; H, C. E.; Der, A. v.; Heinzer, R.; Haba-Rubio, J.; Feketeova, E.; Högl, B.; Frauscher, B.; Benetó, A.; Khatami, R.; Cañellas, F.; Pfister, C.; Scholz, S.; Billiard, M.; Baumann, C. R.; Ercilla, G.; Verduijn, W.; J, F. H.; Dubois, V.; Nowak, J.; Eberhard, H.; Pradervand, S.; Hor, C. N.; Testi, M.; Tiercy, J.; Kutalik, Z.

Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.Retrospective case-control study.A recent study showed that over 76\% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication.For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included.None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified.An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

2014 - Erratum: CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy (Science Translational Medicine (2013) 5 (216ra176) ) [Articolo su rivista]
De La Herran-Arita, A. K.; Kornum, B. R.; Mahlios, J.; Jiang, W.; Lin, L.; Hou, T.; Macaubas, C.; Einen, M.; Plazzi, G.; Crowe, C.; Newell, E. W.; Davis, M. M.; Mellins, E. D.; Mignot, E.

2014 - Erratum to: The timing between REM sleep behavior disorder and Parkinson's disease (Sleep Breath DOI: 10.1007/s11325-013-0887-3) [Articolo su rivista]
Ferri, R.; Cosentino, F. I. I.; Pizza, F.; Arico, D.; Plazzi, G.

2014 - Facing emotions in narcolepsy with cataplexy: haemodynamic and behavioural responses during emotional stimulation [Articolo su rivista]
Zambotti, M. d.; Pizza, F.; Covassin, N.; Vandi, S.; Cellini, N.; Stegagno, L.; Plazzi, G.

Narcolepsy with cataplexy is a complex sleep disorder that affects the modulation of emotions: cataplexy, the key symptom of narcolepsy, is indeed strongly linked with emotions that usually trigger the episodes. Our study aimed to investigate haemodynamic and behavioural responses during emotional stimulation in narco-cataplexy. Twelve adult drug-naive narcoleptic patients (five males; age: 33.3 ± 9.4 years) and 12 healthy controls (five males; age: 30.9 ± 9.5 years) were exposed to emotional stimuli (pleasant, unpleasant and neutral pictures). Heart rate, arterial blood pressure and mean cerebral blood flow velocity of the middle cerebral arteries were continuously recorded using photoplethysmography and Doppler ultrasound. Ratings of valence and arousal and coping strategies were scored by the Self-Assessment Manikin and by questionnaires, respectively. Narcoleptic patients' haemodynamic responses to pictures overlapped with the data obtained from controls: decrease of heart rate and increase of mean cerebral blood flow velocity regardless of pictures' content, increase of systolic blood pressure during the pleasant condition, and relative reduction of heart rate during pleasant and unpleasant conditions. However, when compared with controls, narcoleptic patients reported lower arousal scores during the pleasant and neutral stimulation, and lower valence scores during the pleasant condition, respectively, and also a lower score at the 'focus on and venting of emotions' dimensions of coping. Our results suggested that adult narcoleptic patients, compared with healthy controls, inhibited their emotion-expressive behaviour to emotional stimulation, and that may be related to the development of adaptive cognitive strategies to face emotions avoiding cataplexy.

2014 - From phenomenology to neurophysiological understanding of hallucinations in children and adolescents [Articolo su rivista]
Jardri, R.; Bartels-Velthuis, A. A.; Debbané, M.; Jenner, J. A.; Kelleher, I.; Dauvilliers, Y.; Plazzi, G.; Demeulemeester, M.; David, C. N.; Rapoport, J.; Dobbelaere, D.; Escher, S.; Fernyhough, C.

Typically reported as vivid, multisensory experiences which may spontaneously resolve, hallucinations are present at high rates during childhood. The risk of associated psychopathology is a major cause of concern. On the one hand, the risk of developing further delusional ideation has been shown to be reduced by better theory of mind skills. On the other hand, ideas of reference, passivity phenomena, and misidentification syndrome have been shown to increase the risk of self-injury or heteroaggressive behaviors. Cognitive psychology and brain-imaging studies have advanced our knowledge of the mechanisms underlying these early-onset hallucinations. Notably, specific functional impairments have been associated with certain phenomenological characteristics of hallucinations in youths, including intrusiveness and the sense of reality. In this review, we provide an update of associated epidemiological and phenomenological factors (including sociocultural context, social adversity, and genetics, considered in relation to the psychosis continuum hypothesis), cognitive models, and neurophysiological findings concerning hallucinations in children and adolescents. Key issues that have interfered with progress are considered and recommendations for future studies are provided.

2014 - HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency [Articolo su rivista]
Han, F.; Lin, L.; Schormair, B.; Pizza, F.; Plazzi, G.; Ollila, H. M.; Nevsimalova, S.; Jennum, P.; Knudsen, S.; Winkelmann, J.; Coquillard, C.; Babrzadeh, F.; Strom, T. M.; Wang, C.; Mindrinos, M.; Vina, M. F.; Mignot, E.

To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4\% of cases with cataplexy, and in 20.0\% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7\% [0.8\%-3.4\%] of all cases with cataplexy and 1.8\% [0.8\%-3.4\%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.

2014 - Idiopathic recurrent stupor: Munchausen by proxy and medical litigation [Articolo su rivista]
Plazzi, G.; Rye, D.; Vignatelli, L.; Riva, R.; Lugaresi, E.

2014 - Impact of acute administration of sodium oxybate on nocturnal sleep polysomnography and on multiple sleep latency test in narcolepsy with cataplexy [Articolo su rivista]
Plazzi, G.; Pizza, F.; Vandi, S.; Aricò, D.; Bruni, O.; Dauvilliers, Y.; Ferri, R.

To analyze the acute effects of sodium oxybate (SO) on polysomnographic night-time recordings (PSG) and multiple sleep latency test (MSLT) on patients with narcolepsy with cataplexy (NC).Sixteen NC adult patients were recruited, together with 16 normal controls. Two consecutive PSG followed by two MSLT sessions were carried out, before and during the first night of SO assumption, respectively.The administration of SO was followed by a significant decrease in number of stage shifts and awakenings, wakefulness after sleep onset, and percentage of sleep stage 1. Sleep efficiency and slow wave sleep percentage increased. REM latency decreased significantly from 73 to 12 min. Cyclic alternating pattern (CAP) rate remained unchanged but the percentage of CAP A3 subtypes decreased. The number of CAP A3 subtypes per hour of NREM sleep decreased significantly, whereas that of A1 remained unchanged. The duration of A1 and A3 subtypes was slightly increased. Chin muscle tone was not modified by SO as well as periodic leg movements during sleep, but their periodicity index decreased, becoming similar to that of controls. MSLT sleep latency also significantly improved after SO intake.The administration of SO in NC patients is followed by immediate important and complex effects on PSG parameters and MSLT, including an evident (over)increase in slow wave sleep, which does not display a physiological microstructure, a moderate decrease in periodic and isolated LMs, possibly mediated by a disinhibited dopaminergic neuronal activity, and an improvement on daytime mean sleep latency at the MSLT.

2014 - Lower wake resting sympathetic and cardiovascular activities in narcolepsy with cataplexy [Articolo su rivista]
V., Donadio; Liguori, Rocco; Vandi, Stefano; Pizza, Fabio; Y., Dauvilliers; V., Leta; M. P., Giannoccaro; Baruzzi, Agostino; Plazzi, Giuseppe

Conflicting data have been reported on resting autonomic tone in narcolepsy with cataplexy (NC), including reduced or increased sympathetic activity; to settle this important point, we aimed to measure the resting sympathetic and cardiovascular activities in patients with NC by direct microneurographic monitoring of muscle sympathetic nerve activity (MSNA) during wakefulness.We studied 19 untreated patients with established criteria for NC and hypocretin deficiency and 19 sex- and age-matched healthy subjects. Subjects underwent resting microneurographic recording of MSNA from peroneal nerve and heart rate (HR), whereas blood pressure (BP) was measured with a sphygmomanometer after the end of microneurographic recording. The awake state was continuously monitored by an ambulatory polygraphic recorder.Patients with NC displayed lower resting MSNA, HR, and BP values than controls. Pearson regression analysis showed a correlation between CSF hypocretin-1 level and MSNA or HR, whereas no correlation was found with BP; however, patients with virtually absent hypocretin-1 displayed lower BP than patients with the highest hypocretin-1 value.(1) Patients with NC displayed decreased resting MSNA, HR, and BP during wakefulness, lowering their cardiovascular risk profile; (2) CSF hypocretin-1 deficiency was correlated with MSNA or HR, supporting a direct effect of hypocretin on autonomic regulation; (3) although hypocretin-1 was not correlated with BP, patients with absent hypocretin-1 had lower BP.

2014 - Mitochondrial abnormalities in fibroblasts carrying DNMT1 mutations [Abstract in Atti di Convegno]
Maresca, Alessandra; Zanna, Claudia; Del Dotto, V; Caporali, Leonardo; Moghadam, Kk; Pizza, Fabio; LA MORGIA, Chiara; Melberg, A; Mignot, E; Plazzi, Giuseppe; Carelli, Valerio

ABSTRACT: Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) and hereditary sensory neuropathy with dementia and hearing loss (HSE-IN) are rare neurodegenerative syndromes recently linked to dominant pathogenic mutations in the DNA methyltransferase 1 (DNMT1) gene. ADCA-DN and HSN-IE phenotypes share some features such as optic atrophy, deafness, cerebellar ataxia, peripheral neuropathy and narcolepsy. Moreover, both ADCA-DN and HSN-IE phenotypes present clinical features typical of mitochondrial diseases and some biochemical evidence of mitochondrial dysfunction in muscle of ADCA-DN patients was previously reported. Interestingly, DNMT1 has been recently recognized as responsible for mitochondrial DNA (mtDNA) methylation, in addition to nuclear DNA methylation, suggesting that DNMT1 mutations may directly affect mtDNA, supporting also the hypothesis of mitochondrial dysfunction in ADCA-DN and HSN-IE. To investigate the pathogenic mechanisms of DNMT1 mutations, and how these genetic defects may affect mitochondrial function, we studied fibroblasts from ADCA-DN and HSE-IN families carrying four different mutations in DNMT1 (p.A570V, p.G605A, p.V606F, p.P507R). All mutants showed a significant increase of about 1,5 fold in DNMT1 mRNA expression and a significant reduction of about 40% in the global DNA methyltransferase activity, as evaluated in total cellular protein extracts, compared to controls. Analysis of mitochondrial transcription revealed a significant increase of mitochondrial gene expression in the mutants compared to controls. We observed the mitochondrial network after 48 hours of growth in galactose medium, finding a marked decrease in the percentage of cells with filamentous mitochondria and, concomitantly, an increased number of cells with fragmented mitochondria. These preliminary data demonstrate that mutations in DNMT1 responsible for ADCA-DN and HSE-IN may produce a defect in the methyltransferase activity, possibly causing a reduction in mtDNA methylation, which in turn leads to the increased mtDNA transcription. Moreover, the network fragmentation induced by galactose suggests a mitochondrial defect impinging on the mito-network dynamics.

2014 - Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination [Articolo su rivista]
Partinen, M.; Kornum, B. R.; Plazzi, G.; Jennum, P.; Julkunen, I.; Vaarala, O.

Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12-16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger.

2014 - Narcolepsy is a common phenotype in HSAN IE and ADCA-DN [Articolo su rivista]
Moghadam, Kk; Pizza, F; La Morgia, C; Franceschini, C; Tonon, C; Lodi, R; Barboni, P; Seri, M; Ferrari, S; Liguori, R; Donadio, V; Parchi, P; Cornelio, F; Inzitari, D; Mignarri, A; Capocchi, G; Dotti, Mt; Winkelmann, J; Lin, L; Mignot, E; Carelli, V; Plazzi, G

We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.

2014 - Neuropsychological findings in childhood narcolepsy [Articolo su rivista]
Posar, A.; Pizza, F.; Parmeggiani, A.; Plazzi, G.

Narcolepsy with cataplexy is a severely disabling disorder very often arising in childhood. Data on neuropsychological impairment in children are scant. We administered standardized neuropsychological tests to 13 children with narcolepsy with cataplexy. Overall, our patients displayed multiple patterns of cognitive and behavioral dysfunction, and often academic failure (7 cases out of 13). All children had a normal full intelligence quotient (IQ), but 3 patients presented a significantly higher and 2 a significantly lower Verbal IQ compared to Performance IQ, respectively. Mean sleep latency was significantly correlated (P < .05) to alertness functions. Eight patients displayed behavioral problems: emotional symptoms and conduct problems prevailed. Childhood narcolepsy with cataplexy represents a risk factor for subtle and heterogeneous cognitive impairments potentially resulting in academic failure, despite the normal IQ. These children also have a certain psychopathological risk. All this seems to be at least partially detached from the direct effects of daytime sleepiness.

2014 - Nocturnal frontal lobe epilepsy [Articolo su rivista]
Nobili, L.; Proserpio, P.; Combi, R.; Provini, F.; Plazzi, G.; Bisulli, F.; Tassi, L.; Tinuper, P.

Nocturnal frontal lobe epilepsy (NFLE) is a syndrome of heterogeneous etiology, characterized by the occurrence of sleep-related seizures with different complexity and duration. Genetic, lesional, and cryptogenetic NFLE forms have been described. NFLE is generally considered a benign clinical entity, although severe, drug-resistant forms do exist. A significant proportion of sleep-related complex motor seizures, hardly distinguishable from NFLE, originate outside the frontal lobe. Moreover, the distinction of NFLE from the non-rapid eye movement arousal parasomnias may be challenging. A correct diagnosis of NFLE should be based on a diagnostic approach that includes the anamnestic, video-polysomnographic, morphological, and genetic aspects. Studies on the relationships between genes, arousal regulatory mechanisms, and epileptogenesis, using both clinical and experimental models of NFLE might provide key insights in the interrelationship between sleep and epilepsy.

2014 - Parasomnias [Capitolo/Saggio]
Plazzi, G.; Nobili, L.

The term parasomnias was coined by the French neurologist Henry Roger during the lessons he gave in Marseille (France) between the years 1900 and 1931 and published in his monograph in 1932. With this term he referred to unusual, not rare behaviors appearing during sleep due to negligible dysfunctions of the "hypnic function"...

2014 - Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1 [Articolo su rivista]
Moghadam, K. K.; Pizza, F.; Tonon, C.; Lodi, R.; Carelli, V.; Poli, F.; Franceschini, C.; Barboni, P.; Seri, M.; Ferrari, S.; Morgia, C. L.; Testa, C.; Cornelio, F.; Liguori, R.; Winkelmann, J.; Lin, L.; Mignot, E.; Plazzi, G.

We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed.History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities.The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.

2014 - Primary progressive narcolepsy type 1: the other side of the coin [Articolo su rivista]
Pizza, F.; Vandi, S.; Liguori, R.; Parchi, P.; Avoni, P.; Mignot, E.; Plazzi, G.

2014 - Remitting Tics and Narcolepsy Overlap Associated with Streptococcal Infection: A Case Report [Articolo su rivista]
Baiardi, Simone; Antelmi, Elena; Filardi, Marco; Pizza, Fabio; Vandi, Stefano; Veggiotti, Pierangelo; Liguori, Rocco; Plazzi, Giuseppe


2014 - Response to "Dante's syncopes" [Articolo su rivista]
Plazzi, G.

2014 - Sleeping with spinal cord injury [Articolo su rivista]
Pizza, F.; Plazzi, G.


2014 - Sleep-related violence and sexual behavior in sleep: a systematic review of medical-legal case reports [Articolo su rivista]
Ingravallo, F.; Poli, F.; Gilmore, E. V.; Pizza, F.; Vignatelli, L.; Schenck, C. H.; Plazzi, G.

To review systematically medical-legal cases of sleep-related violence (SRV) and sexual behavior in sleep (SBS).We searched Pubmed and PsychINFO (from 1980 to 2012) with pre-specified terms. We also searched reference lists of relevant articles.Case reports in which a sleep disorder was purported as the defense during a criminal trial and in which information about the forensic evaluation of the defendant was provided.Information about legal issues, defendant and victim characteristics, circumstantial factors, and forensic evaluation was extracted from each case. A qualitative-comparative assessment of cases was performed.Eighteen cases (9 SRV and 9 SBS) were included. The charge was murder or attempted murder in all SRV cases, while in SBS cases the charge ranged from sexual touching to rape. The defense was based on sleepwalking in 11 of 18 cases. The trial outcome was in favor of the defendant in 14 of 18 cases. Defendants were relatively young males in all cases. Victims were usually adult relatives of the defendants in SRV cases and unrelated young girls or adolescents in SBS cases. In most cases the criminal events occurred 1-2 hours after the defendant's sleep onset, and both proximity and other potential triggering factors were reported. The forensic evaluations widely differed from case to case.SRV and SBS medical-legal cases did not show apparent differences, except for the severity of the charges and the victim characteristics. An international multidisciplinary consensus for the forensic evaluation of SRV and SBS should be developed as an urgent priority.

2014 - Sympathetic and cardiovascular changes during sleep in narcolepsy with cataplexy patients [Articolo su rivista]
V., Donadio; Liguori, Rocco; Vandi, Stefano; M. P., Giannoccaro; Pizza, Fabio; V., Leta; Plazzi, Giuseppe

Neural mechanisms underlying sleep-onset rapid eye movement (REM) periods (SOREMPs) in narcolepsy and the role of hypocretin in driving sympathetic changes during sleep are misunderstood. We aimed to characterize autonomic changes during sleep in narcolepsy with cataplexy (NC) patients to clarify the nature of SOREMP events and the effect of hypocretin deficiency on sympathetic activity during sleep.We observed 13 hypocretin-deficient NC patients and five healthy controls who underwent nocturnal video-polysomnography (v-PSG) with blood pressure (BP) recording, heart rate (HR), skin sympathetic activity (SSA), and muscle sympathetic nerve activity (MSNA) from the peroneal nerve by microneurography.Compared to wake, control participants displayed a progressive significant decrease of BP and sympathetic activities during nonrapid eye movement (NREM) sleep and an increase of autonomic activity during REM sleep, as expected. NC patients showed: (1) a decrease of sympathetic activities during SOREMP comparable to NREM sleep stage 1 (N1) but in contrast to the increased activity typical of REM sleep; and (2) physiologic sympathetic change during the following sleep stages with a progressive decrease during NREM sleep stage 2 (N2) and NREM sleep stage 3 (N3) and a clear increase in REM sleep, though BP did not show the physiologic decrease during sleep (nondipper pattern).SOREMPs in NC patients lack the sympathetic activation occurring during physiologic REM sleep, thus suggesting a dissociated REM sleep condition. In addition, our data indicated that hypocretin plays a limited role in the regulation of sympathetic changes during sleep.

2014 - The hypocretin system and psychiatric disorders [Articolo su rivista]
Pizza, F.; Magnani, M.; Indrio, C.; Plazzi, G.

The hypocretin system is constituted by a small group of hypothalamic neurons with widespread connections within the entire central nervous system producing two neuropeptides involved in several key physiological functions such as the regulation of sleep and wakefulness, motor control, autonomic functions, metabolism, feeding behavior, and reward. Narcolepsy with cataplexy is a neurological disorder regarded as a disease model for the selective hypocretin system damage, and also shares several psychopatological traits and comorbidities with psychiatric disorders. We reviewed the available literature on the involvement of the hypocretin system in psychiatric nosography. Different evidences such as cerebrospinal hypocretin-1 levels, genetic polymorphisms of the neuropeptides or their receptors, response to treatments, clinical, experimental and functional data directly or indirectly linked the hypocretin system to schizophrenia, mood, anxiety and eating disorders, as well as to addiction. Future genetic and pharmacological studies will disentangle the hypocretin system role in the field of psychiatry.

2014 - The timing between REM sleep behavior disorder and Parkinson's disease [Articolo su rivista]
Ferri, R.; I, F. I.; Pizza, F.; Aricò, D.; Plazzi, G.

In Parkinson's disease (PD) patients, REM sleep behavior disorder (RBD) might precede PD or develop with or after the onset of PD. No previous study has explored differences between these two groups. The aim of this study was therefore to compare clinical features and REM sleep chin electromyographic patterns between patients in whom RBD heralded PD and those in whom RBD occurrence coincided with or followed the clinical manifestations of PD.Twenty-seven consecutive PD patients (mean age 67.9 years) were enrolled. Detailed clinical, laboratory, and polysomnographic studies were obtained in all participants.Sixteen of the 27 patients were affected by RBD. These had a significantly higher stage of PD and took significantly higher doses of dopaminergic therapy; their disease duration tended to be longer, and their cognitive status tended to be lower. PD patients in whom RBD preceded PD (n = 6) did not differ from PD patients without RBD in disease parameters, while PD patients in whom RBD developed with or after PD (n = 10) showed a significantly higher disease stage, took significantly higher dopaminergic therapy, and had a longer disease duration.Our findings are compatible with the hypothesis that patients in whom RBD precedes, or does not precede, PD might constitute two possibly distinct clinical and physiopathological groups, based on different progressive neuropathological sequences of events.

2013 - Cardiovascular variability as a function of sleep-wake behaviour in narcolepsy with cataplexy [Articolo su rivista]
Silvani, Alessandro; D., Grimaldi; Barletta, Giorgio; S., Bastianini; Vandi, Stefano; Pierangeli, Giulia; Plazzi, Giuseppe; Cortelli, Pietro

Hypocretin/orexin signalling varies among sleep-wake behaviours, impacts upon cardiovascular autonomic control and is impaired in patients with narcolepsy with cataplexy (NC). However, evidence concerning disturbed cardiovascular autonomic control in NC patients is contrasting, and limited mainly to waking behaviour. We thus investigated whether control of cardiovascular variability is altered in NC patients during wakefulness preceding sleep, light (1-2) and deep (3-4) stages of non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. Polysomnographic recordings and finger blood pressure measurements were performed on nine drug-free male NC patients and nine matched healthy control subjects during spontaneous sleep-wake behaviour in a standardized laboratory environment. Indices of autonomic function were computed based on spontaneous fluctuations of systolic blood pressure (SBP) and heart period (HP). During wakefulness before sleep, NC patients showed significant decreases in indices of vagal HP modulation, cardiac baroreflex sensitivity and amplitude of central autonomic (feed-forward) cardiac control compared with control subjects. During NREM sleep, the negative correlation between HP and subsequent SBP values was greater in NC patients than in control subjects, suggesting a greater contribution of central autonomic commands to cardiac control. Collectively, these results provide preliminary evidence that autonomic control of cardiac variability by baroreflex and central autonomic (feed-forward) mechanisms is altered in NC patients during spontaneous sleep-wake behaviour, and particularly during wakefulness before sleep.

2013 - CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to A 2009 h1n1 influenza a epitope in narcolepsy [Articolo su rivista]
De La Herran-Arita, A. K.; Kornum, B. R.; Mahlios, J.; Jiang, W.; Lin, G.; Hou, T.; Macaubas, C.; Einen, M.; Plazzi, G.; Crowe, C.; Newell, E. W.; Davis, M. M.; Mellins, E. D.; Mignot, E.

Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)-DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eyemovement sleep abnormalities. It is caused by the loss of ∼70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56-68 and HCRT87-99, that activated a subpopulation of CD4+ T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56-68- and HCRT87-99-reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275-287, with homology to HCRT56-68 and HCRT87-99. In vitro stimulation of narcolepsy CD4+ T cells with pH1N1 proteins or pHA1 275-287 increased the frequency of HCRT56-68- and HCRT87-99-reactive T cells. Our data indicate the presence of CD4+ T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275-287.

2013 - Childhood narcolepsy with cataplexy: a newly reported phenotype of an old disease? [Articolo su rivista]
Plazzi, G.; Pizza, F.


2013 - Clinical and polysomnographic course of childhood narcolepsy with cataplexy [Articolo su rivista]
Pizza, F.; Franceschini, C.; Peltola, H.; Vandi, S.; Finotti, E.; Ingravallo, F.; Nobili, L.; Bruni, O.; Lin, L.; Edwards, M. J.; Partinen, M.; Dauvilliers, Y.; Mignot, E.; Bhatia, K. P.; Plazzi, G.

Our aim was to investigate the natural evolution of cataplexy and polysomnographic features in untreated children with narcolepsy with cataplexy. To this end, clinical, polysomnographic, and cataplexy-video assessments were performed at diagnosis (mean age of 10 ± 3 and disease duration of 1 ± 1 years) and after a median follow-up of 3 years from symptom onset (mean age of 12 ± 4 years) in 21 children with narcolepsy with cataplexy and hypocretin 1 deficiency (tested in 19 subjects). Video assessment was also performed in two control groups matched for age and sex at first evaluation and follow-up and was blindly scored for presence of hypotonic (negative) and active movements. Patients' data at diagnosis and at follow-up were contrasted, compared with controls, and related with age and disease duration. At diagnosis children with narcolepsy with cataplexy showed an increase of sleep time during the 24 h; at follow-up sleep time and nocturnal sleep latency shortened, in the absence of other polysomnographic or clinical (including body mass index) changes. Hypotonic phenomena and selected facial movements decreased over time and, tested against disease duration and age, appeared as age-dependent. At onset, childhood narcolepsy with cataplexy is characterized by an abrupt increase of total sleep over the 24 h, generalized hypotonia and motor overactivity. With time, the picture of cataplexy evolves into classic presentation (i.e., brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases, returning to more age-appropriate levels.

2013 - Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study [Articolo su rivista]
Luca, G.; Haba-Rubio, J.; Dauvilliers, Y.; Lammers, G.; Overeem, S.; Donjacour, C. E.; Mayer, G.; Javidi, S.; Iranzo, A.; Santamaria, J.; Peraita-Adrados, R.; Hor, H.; Kutalik, Z.; Plazzi, G.; Poli, F.; Pizza, F.; Arnulf, I.; Lecendreux, M.; Bassetti, C.; Mathis, J.; Heinzer, R.; Jennum, P.; Knudsen, S.; Geisler, P.; Wierzbicka, A.; Feketeova, E.; Pfister, C.; Khatami, R.; Baumann, C.; Tafti, M.; (EU-NN)., European Narcolepsy Network

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

2013 - Corrigendum to "Effects of long-term use of clonazepam on nonrapid eye movement sleep patterns in rapid eye movement sleep behavior disorder" [Sleep Med 14 (5) (2013) 399-406] [Articolo su rivista]
Ferri, R.; Zucconi, M.; Marelli, S.; Plazzi, G.; Schenck, C. H.; Ferini-Strambi, L.

2013 - Dante's description of narcolepsy [Articolo su rivista]
Plazzi, G.

Sleep, sleepiness, and dreaming are expressed throughout Dante Alighieri's (1265-1321) the Divine Comedy from the start of his journey through the afterlife. In the book, Dante complains that he is "full of sleep," and he experiences sudden wake-dreaming transitions, short and refreshing naps, visions and hallucinations, unconscious behaviors, episodes of muscle weakness, and falls which are always triggered by strong emotions. Taken together these signs are highly reminiscent of narcolepsy, a term coined in 1880 by Gélineau to define a disease consisting of daytime irresistible sleep episodes with remarkable dream mentation, sleep paralysis, hallucinations, and cataplexy (falls triggered by strong emotions). Sleep, sleepiness, and episodes of sudden weakness triggered by emotions are Dante's literary fingerprints from his earliest works, pointing to a lifelong autobiographic trait. In the 19th century, Cesare Lombroso speculated that Dante had epilepsy, as he had suffered from frequent spells and hallucinations. However, the multiple emotionally triggered falls Dante experienced in the Divine Comedy contrast with the epileptic seizure he depicted in one of the damned individuals. It is possible that Dante may have intuitively grasped the main features of narcolepsy, but it also is plausible that Dante's sleep, dreams, hallucinations, and falls are clues to a lifelong pathologic trait and that Dante may have known of or had narcolepsy.

2013 - Daytime continuous polysomnography predicts MSLT results in hypersomnias of central origin [Articolo su rivista]
Pizza, F.; Moghadam, K. K.; Vandi, S.; Detto, S.; Poli, F.; Mignot, E.; Ferri, R.; Plazzi, G.

In the diagnostic work-up of hypersomnias of central origin, the complaint of excessive daytime sleepiness should be objectively confirmed by MSLT findings. Indeed, the features and diagnostic utility of spontaneous daytime sleep at 24 h continuous polysomnography (PSG) have never been investigated. We compared daytime PSG features to MSLT data in 98 consecutive patients presenting with excessive daytime sleepiness and with a final diagnosis of narcolepsy with cataplexy/hypocretin deficiency (n = 39), narcolepsy without cataplexy (n = 7), idiopathic hypersomnia without long sleep time (n = 19), and hypersomnia with normal sleep latency at MSLT (n = 33). Daytime sleep time was significantly higher in narcolepsy-cataplexy but similar in the other groups. Receiver operating characteristics (ROC) curves showed that the number of naps during daytime PSG predicted a mean sleep latency =8 min at MSLT with an area under the curve of 0.67 +/- 0.05 (P = 0.005). The number of daytime sleep-onset REM periods (SOREMPs) in spontaneous naps strikingly predicted the scheduled occurrence of two or more SOREMPs at MSLT, with an area under the ROC curve of 0.93 +/- 0.03 (P < 10-12). One spontaneous SOREMP during daytime had a sensitivity of 96% with specificity of 74%, whereas two SOREMPs had a sensitivity of 75%, with a specificity of 95% for a pathological REM sleep propensity at MSLT. The features of spontaneous daytime sleep well correlated with MSLT findings. Notably, the occurrence of multiple spontaneous SOREMPs during daytime clearly identified patients with narcolepsy, as well as during the MSLT.

2013 - Effects of long-term use of clonazepam on nonrapid eye movement sleep patterns in rapid eye movement sleep behavior disorder [Articolo su rivista]
Ferri, R.; Zucconi, M.; Marelli, S.; Plazzi, G.; Schenck, C. H.; Ferini-Strambi, L.

Objective: We aim to analyze in detail the characteristics of nonrapid eye movement (NREM) sleep in drug-free patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). We compare drug-free iRBD patients to both normal controls and drug-free patients with narcolepsy/RBD and evaluate the changes following the long-term use of bedtime clonazepam. Participants and methods: Forty-six participants were recruited: 15 with iRBD (13 men, 2 women; mean age, 65.8±4.39years), 13 with narcolepsy/RBD (10 men, 3 women; mean age, 63.0±6.73 years), and 18 normal controls (10 men, 8 women; mean age 69.4±7.72. years). Sleep was video polysomnographically recorded and the RBD severity scale (RBDSS) was obtained. Chin electromyography (EMG) amplitude was quantitatively assessed and the atonia index was computed. Additionally, NREM sleep instability was evaluated using an automatic quantitative analysis. Participants with iRBD were re-evaluated after 2.75±1.62. years of regular therapy with 0.5 to 1-mg clonazepam at bedtime. Results: Slow transient electroencephalography (EEG) events were increased in iRBD and decreased in narcolepsy/RBD, while fast transient events decreased in iRBD and increased in narcolepsy/RBD. During rapid eye movement (REM) sleep the atonia index was reduced in both iRBD and narcolepsy/RBD groups and during NREM sleep atonia index was increased in iRBD participants, remaining low in narcolepsy/RBD participants. After long-term therapy with clonazepam, wakefulness after sleep onset was decreased together with an increase in both slow-wave sleep (SWS) and sleep stage 2, in which the latter reached statistical significance; sleep stages 1 and 2 instability significantly decreased and the duration of EEG transients also slightly but significantly decreased. Finally, chin tone was not modified by clonazepam. Conclusions: Our study confirms that clonazepam modifies some aspects of NREM sleep in iRBD participants with a decrease in its instability. Moreover, we also show that a complex modification of sleep chin atonia exists in these participants, which also involves NREM sleep; for iRBD more complex neuropathologic models encompassing REM sleep and NREM sleep mechanisms are needed.

2013 - Electroencephalogram paroxysmal θ characterizes cataplexy in mice and children [Articolo su rivista]
Vassalli, A.; Dellepiane, J. M.; Emmenegger, Y.; Jimenez, S.; Vandi, S.; Plazzi, G.; Franken, P.; Tafti, M.

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement-sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5-2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring.

2013 - Genetics of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [Capitolo/Saggio]
Moghadam, K. K.; Plazzi, G.

Nocturnal frontal lobe epilepsy (NFLE) is a heterogeneous clinical syndrome characterized by clusters of hyperkinetic motor seizures of frontal semiology appearing from sleep, which vary in intensity and duration. The onset of the epilepsy is usually during childhood or adolescence and the disorder is lifelong but not progressive....

2013 - High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy [Articolo su rivista]
Poli, F.; Pizza, F.; Mignot, E.; Ferri, R.; Pagotto, U.; Taheri, S.; Finotti, E.; Bernardi, F.; Pirazzoli, P.; Cicognani, A.; Balsamo, A.; Nobili, L.; Bruni, O.; Plazzi, G.

We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses.Cross-sectional on consecutive recruitment.Hospital sleep center and pediatric unit.Forty-three children and adolescents with NC versus 52 age-matched obese children as controls.N/A.Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74\%) and a higher occurrence of precocious puberty (17\%) than obese controls (1.9\%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41\%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence.NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management.

2013 - ImmunoChip study implicates antigen presentation to T cells in narcolepsy [Articolo su rivista]
J., Faraco; L., Lin; B. R., Kornum; E. E., Kenny; G., Trynka; M., Einen; T. J., Rico; P., Lichtner; Y., Dauvilliers; I., Arnulf; M., Lecendreux; S., Javidi; P., Geisler; G., Mayer; Pizza, Fabio; Poli, Francesca; Plazzi, Giuseppe; S., Overeem; G. J., Lammers; D., Kemlink; K., Sonka; S., Nevsimalova; G., Rouleau; A., Desautels; J., Montplaisir; B., Frauscher; L., Ehrmann; B., Högl; P., Jennum; P., Bourgin; R., Peraita Adrados; A., Iranzo; C., Bassetti; W., Chen; P., Concannon; S. D., Thompson; V., Damotte; B., Fontaine; M., Breban; C., Gieger; N., Klopp; P., Deloukas; C., Wijmenga; J., Hallmayer; S., Onengut Gumuscu; S. S., Rich; J., Winkelmann; E., Mignot

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

2013 - Indice dicotomico e qualità del sonno [Abstract in Atti di Convegno]
Natale, V.; Innominato, P.; Martoni, M.; Fusté, I.; Plazzi, G.; Filardi, M.; Lévi, F.

2013 - Influence of cytochrome P450 and ABCB1 genetic polymorphisms on drug efficacy in narcolepsy with cataplexy [Abstract in Rivista]
Poli, F.; Moresco, M.; Riccardi, L. N.; Plazzi, G.; Ingravallo, F.; Pelotti, S.

2013 - Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging [Articolo su rivista]
Rizzo, G.; Manners, D.; Testa, C.; Tonon, C.; Vetrugno, R.; Marconi, S.; Plazzi, G.; Pizza, F.; Provini, F.; Malucelli, E.; Gramegna, L. L.; Lodi, R.

BACKGROUND: The objective of this study was to use phase imaging to evaluate brain iron content in patients with idiopathic restless legs syndrome (RLS). METHODS: Fifteen RLS patients and 15 healthy controls were studied using gradient-echo imaging. Phase analysis was performed on localized brain regions of interest selected on phase maps, sensitive to paramagnetic tissue. Differences between the 2 subject groups were evaluated using ANCOVA including age as a covariate. RESULTS: Significantly higher phase values were present in the RLS patients compared with healthy controls at the level of the substantia nigra, thalamus, putamen, and pallidum, indicating reduced iron content in several regions of the brain of the patients. CONCLUSIONS: We have used MRI phase analysis to study brain iron content in idiopathic RLS in vivo for the first time. Our results support the hypothesis of reduced brain iron content in RLS patients, which may have an important role in the pathophysiology of the disorder. © 2013 Movement Disorder Society.

2013 - Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies [Articolo su rivista]
Maurovich-Horvat, E.; Kemlink, D.; Högl, B.; Frauscher, B.; Ehrmann, L.; Geisler, P.; Ettenhuber, K.; Mayer, G.; Peraita-Adrados, R.; Calvo, E.; Lammers, G. J.; Der, A. V.; Ferini-Strambi, L.; Plazzi, G.; Poli, F.; Dauvilliers, Y.; Jennum, P.; Leonthin, H.; Mathis, J.; Wierzbicka, A.; Puertas, F. J.; Beitinger, P. A.; Arnulf, I.; Riha, R. L.; Tormášiová, M.; Slonková, J.; Nevšímalová, S.; Sonka, K.; Network., the European Narcolepsy

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1\% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

2013 - Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation [Articolo su rivista]
Poli, F.; Overeem, S.; Lammers, G. J.; Plazzi, G.; Lecendreux, M.; Bassetti, C. L.; Dauvilliers, Y.; Keene, D.; Khatami, R.; Li, Y.; Mayer, G.; Nohynek, H.; Pahud, B.; Paiva, T.; Partinen, M.; Scammell, T. E.; Shimabukuro, T.; Sturkenboom, M.; Dinther, K. v.; Wiznitzer, M.; Bonhoeffer, J.


2013 - Narcolepsy with cataplexy mimicry: the strange case of two sisters [Articolo su rivista]
Pizza, F.; Vandi, S.; Poli, F.; Moghadam, K. K.; Franceschini, C.; Bellucci, C.; Cipolli, C.; Ingravallo, F.; Natalini, G.; Mignot, E.; Plazzi, G.

We report on two sisters, 17 and 12 years of age, with clinical features suggesting narcolepsy with cataplexy (NC): daytime sleepiness, spontaneous and emotionally triggered sudden falls to the ground, and overweight/obesity. MSLT showed borderline sleep latency, with 1 and 0 sleep onset REM periods. HLA typing disclosed the DQB1*0602 allele. Video-polygraphy of the spells ruled out NC diagnosis by demonstrating their easy elicitation by suggestion, with wake EEG, electromyographic persistence of muscle tone, and stable presence of tendon reflexes (i.e., pseudo-cataplexy), together with normal cerebrospinal hypocretin-1 levels. Our cases emphasize the need of a clear depiction of cataplexy pattern at the different ages, the usefulness of examining ictal neurophysiology, and collecting all available disease markers in ambiguous cases.

2013 - Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management [Articolo su rivista]
D'Angelo, R.; Morreale, A.; Donadio, V.; Boriani, S.; Maraldi, N.; Plazzi, G.; Liguori, R.

In biology, it is easy to understand how a damaged functional system may generate wrong signals, but why this should happen when the system is disconnected is less clear. For this reason, among other pain syndromes, neuropathic pain (NP) following spinal cord injury (SCI) leaves most questions unanswered.Our purpose is to review current knowledge on NP after SCI, focusing on the mechanisms, assessment and management of the syndrome.The mechanisms responsible for NP following SCI are poorly understood: NP is classically considered a "central pain syndrome" but recent evidence from experimental models reveals a possible "peripheral sensitization". Assessment of NP following SCI is well-established: in addition to clinical evaluation and self-reported scales, many neurophysiological, radiological and microscopic investigations may be performed. The management of NP following SCI is very difficult: evidence of effective drugs is lacking and alternative new treatment approaches yield different outcomes.Recently clinical and instrumental tools have increased our knowledge on NP, suggesting that the discovery of new treatment agents will depend on an explanation of what changes after SCI: future research must point in this direction.

2013 - Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency [Articolo su rivista]
Andlauer, O.; Moore, H.; Jouhier, L.; Drake, C.; Peppard, P. E.; Han, F.; Hong, S.; Poli, F.; Plazzi, G.; O'Hara, R.; Haffen, E.; Roth, T.; Young, T.; Mignot, E.

IMPORTANCE Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically. OBJECTIVE To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency. DESIGN, SETTING, AND PARTICIPANTS Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels. MAIN OUTCOME AND MEASURES Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level. RESULTS Short REML (≤15 minutes) during NPSG was highly specific (99.2\% [95\% CI, 98.5\%-100.0\%] of 516 and 99.6\% [95\% CI, 99.1\%-100.0\%] of 735) but not sensitive (50.6\% [95\% CI, 46.3\%-54.9\%] of 516 and 35.7\% [95\% CI, 10.6\%-60.8\%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95\% CI, 0.771-0.826] and 0.704 [95\% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4\% [95\% CI, 90.4\%-98.3\%] of 132) and similarly sensitive (57.4\% [95\% CI, 48.1\%-66.3\%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95\% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1\% (95\% CI, 83.6\%-97.0\%). CONCLUSIONS AND RELEVANCE Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.

2013 - Polysomnographic study of nocturnal sleep in idiopathic hypersomnia without long sleep time [Articolo su rivista]
Pizza, F; Ferri, R; Poli, F; Vandi, S; Cosentino, Fi; Plazzi, G.

We investigated nocturnal sleep abnormalities in 19 patients with idiopathic hypersomnia without long sleep time (IH) in comparison with two age- and sex- matched control groups of 13 normal subjects (C) and of 17 patients with narcolepsy with cataplexy (NC), the latter considered as the extreme of excessive daytime sleepiness (EDS). Sleep macroand micro- (i.e. cyclic alternating pattern, CAP) structure as well as quantitative analysis of EEG, of periodic leg movements during sleep (PLMS), and of muscle tone during REM sleep were compared across groups. IH and NC patients slept more than C subjects, but IH showed the highest levels of sleep fragmentation (e.g. awakenings), associated with a CAP rate higher than NC during lighter sleep stages and lower than C during slow wave sleep respectively, and with the highest relative amount of A3 and the lowest of A1 subtypes. IH showed a delta power in between C and NC groups, whereas muscle tone and PLMS had normal characteristics. A peculiar profile of microstructural sleep abnormalities may contribute to sleep fragmentation and, possibly, EDS in IH.

2013 - Rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia in narcolepsy [Articolo su rivista]
Dauvilliers, Y.; Jennum, P.; Plazzi, G.

Narcolepsy is a rare disabling hypersomnia disorder that may include cataplexy, sleep paralysis, hypnagogic hallucinations, and sleep-onset rapid eye movement (REM) periods, but also disrupted nighttime sleep by nocturnal awakenings, and REM sleep behavior disorder (RBD). RBD is characterized by dream-enacting behavior and impaired motor inhibition during REM sleep (REM sleep without atonia, RSWA). RBD is commonly associated with neurodegenerative disorders including Parkinsonisms, but is also reported in narcolepsy in up to 60% of patients. RBD in patients with narcolepsy is, however, a distinct phenotype with respect to other RBD patients and characterized also by absence of gender predominance, elementary rather than complex movements, less violent behavior and earlier age at onset of motor events, and strong association to narcolepsy with cataplexy/hypocretin deficiency. Patients with narcolepsy often present dissociated sleep features including RSWA, increased density of phasic chin EMG and frequent shift from REM to NREM sleep, with or without associated clinical RBD. Most patients with narcolepsy with cataplexy lack the hypocretin neurons in the lateral hypothalamus. Tonic and phasic motor activities in REM sleep and dream-enacting behavior are mostly reported in presence of cataplexy. Narcolepsy without cataplexy is a condition rarely associated with hypocretin deficiency. We proposed that hypocretin neurons are centrally involved in motor control during wakefulness and sleep in humans, and that hypocretin deficiency causes a functional defect in the motor control involved in the development of cataplexy during wakefulness and RBD/RSWA/phasic motor activity during REM sleep.

2013 - Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group [Articolo su rivista]
Schenck, C. H.; Montplaisir, J. Y.; Frauscher, B.; Hogl, B.; Gagnon, J.; Postuma, R.; Sonka, K.; Jennum, P.; Partinen, M.; Arnulf, I.; De, V. C.; Dauvilliers, Y.; Luppi, P.; Heidbreder, A.; Mayer, G.; Sixel-Döring, F.; Trenkwalder, C.; Unger, M.; Young, P.; Wing, Y. K.; Ferini-Strambi, L.; Ferri, R.; Plazzi, G.; Zucconi, M.; Inoue, Y.; Iranzo, A.; Santamaria, J.; Bassetti, C.; Möller, J. C.; Boeve, B. F.; Lai, Y. Y.; Pavlova, M.; Saper, C.; Schmidt, P.; Siegel, J. M.; Singer, C.; Louis, E. S.; Videnovic, A.; Oertel, W.

We 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.The 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]).Six 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.The 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.

2013 - Scoring atonia during normal and pathological rapid eye movement sleep: Visual and automatic quantification methods [Articolo su rivista]
Fulda, S.; Plazzi, G.; Ferri, R.

One of the essential features of rapid eye movement (REM) sleep behavior disorder is REM sleep without atonia seen during nocturnal polysomnographic recordings. In this paper we provide an overview about the varied scoring criteria proposed for visual analysis of loss of atonia during REM sleep. The automatic quantification of loss of atonia overcomes many of the limitations of visual scoring and these new approaches are reviewed. Finally, the contributions of these automatic methods to the understanding of the complex mechanisms underlying muscle atonia and motor suppression during REM sleep are briefly illustrated. © 2013 The Authors Sleep and Biological Rhythms © 2013 Japanese Society of Sleep Research.

2013 - Sleep and movement disorders [Articolo su rivista]
M. P., Giannoccaro; Antelmi, Elena; Plazzi, Giuseppe

The aim is to review sleep disturbances in different movement disorders, mainly Parkinson's disease, and highlight current concepts on merging the boundaries between movement disorders and dissociative states of being.Since the observation that rapid eye movement sleep behavior disorder (RBD) may be an early marker of neurodegeneration, many studies focused on this disorder for the opportunity to explore the pathogenetic mechanisms underlying movement disorder and future neuroprotective therapies. It is also increasingly evident that this disorder is a possible marker for incoming dementia and for a general worst prognosis. Mechanisms of excessive daytime sleepiness in Parkinson's disease are still to be clarified and, if the role of hypocretin neuron loss is still doubtful, attention is moving to the role of monoaminergic system disruption. The role of dopamine in circadian rhythm regulation is opening new scenarios, namely the disruption of clock genes expression. Finally, the close relationship between sleep and movement disorder is emerging also in primarly sleep disorders.Recent studies provided new insights into the links between sleep and movement disorder that may simplify the diagnostic process and shed light on the underlying pathophysiological mechanisms.

2013 - Sleep disorders in patients with spinal cord injury [Articolo su rivista]
M. P., Giannoccaro; K. K., Moghadam; Pizza, Fabio; Boriani, Stefano; Maraldi, Nadir; Avoni, Patrizia; A., Morreale; Liguori, Rocco; Plazzi, Giuseppe

Sleep disturbances are globally more frequent in patients with spinal cord injury (SCI) than in the able-bodied population, and could contribute to dysfunction and poor quality of life in these patients. Specific sleep disorders may also contribute to negative health outcomes enhancing cardiovascular risk in a condition that per se increases heart disease related mortality. This review focuses on prevalence, features and treatment of sleep disorders in SCI. Although data on these subjects have been produced, reports on pathophysiology, consequences and treatment of sleep disorders are scarce or contradictory and more studies are required.

2013 - Sleep dynamics beyond traditional sleep macrostructure [Articolo su rivista]
Plazzi, G.; Pizza, F.

2013 - Sleep forensic case reports [Abstract in Rivista]
Ingravallo, F.; Poli, F.; Vignatelli, L.; Pizza, F.; Plazzi, G.

2013 - Sleep-dependent memory consolidation in patients with sleep disorders [Articolo su rivista]
Cipolli, C.; Mazzetti, M.; Plazzi, G.

Sleep can improve the off-line memory consolidation of new items of declarative and non-declarative information in healthy subjects, whereas acute sleep loss, as well as sleep restriction and fragmentation, impair consolidation. This suggests that, by modifying the amount and/or architecture of sleep, chronic sleep disorders may also lead to a lower gain in off-line consolidation, which in turn may be responsible for the varying levels of impaired performance at memory tasks usually observed in sleep-disordered patients. The experimental studies conducted to date have shown specific impairments of sleep-dependent consolidation overall for verbal and visual declarative information in patients with primary insomnia, for verbal declarative information in patients with obstructive sleep apnoeas, and for visual procedural skills in patients with narcolepsy-cataplexy. These findings corroborate the hypothesis that impaired consolidation is a consequence of the chronically altered organization of sleep. Moreover, they raise several novel questions as to: a) the reversibility of consolidation impairment in the case of effective treatment, b) the possible negative influence of altered prior sleep also on the encoding of new information, and c) the relationships between altered sleep and memory impairment in patients with other (medical, psychiatric or neurological) diseases associated with quantitative and/or qualitative changes of sleep architecture.

2013 - The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns [Articolo su rivista]
Wijnans, L.; Lecomte, C.; Vries, C. d.; Weibel, D.; Sammon, C.; Hviid, A.; Svanström, H.; Mølgaard-Nielsen, D.; Heijbel, H.; Dahlström, L. A.; Hallgren, J.; Sparen, P.; Jennum, P.; Mosseveld, M.; Schuemie, M.; Der, N. v.; Partinen, M.; Romio, S.; Trotta, F.; Santuccio, C.; Menna, A.; Plazzi, G.; Moghadam, K. K.; Ferro, S.; Lammers, G. J.; Overeem, S.; Johansen, K.; Kramarz, P.; Bonhoeffer, J.; J, M. C.

In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification.We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom.Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95\% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95\% CI: 1.1-3.1) in Denmark, 6.4 (95\% CI: 4.2-9.7) in Finland and 7.5 (95\% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time.The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

2012 - A preliminary quantitative analysis of REM sleep chin EMG in Parkinson's disease with or without REM sleep behavior disorder [Articolo su rivista]
Ferri, R.; Fulda, S.; Cosentino, F. I.; Pizza, F.; Plazzi, G.

OBJECTIVES: To compare REM sleep chin EMG quantitative features between Parkinson's disease (PD) patients with or without REM sleep behavior disorder (RBD). SUBJECTS AND METHODS: Twenty-seven consecutive PD patients (mean age 67.9 years) and 19 normal controls (mean age 67.5 years) were enrolled. Detailed clinical, laboratory, and polysomnographic studies were obtained in all participants and characteristics of chin electromyographic amplitude during rapid eye movements sleep were analyzed by means of an automatic quantitative approach (Atonia Index). RESULTS: Sixteen of the 27 patients were affected by RBD. An Atonia Index below 0.90 showed high sensitivity (0.938) and specificity (0.909) for the diagnosis of RBD within the group of PD patients. CONCLUSION: This study recommends the Atonia Index as an objective measure to support and aid the diagnosis of RBD in PD.

2012 - A quantitative analysis of the submentalis muscle electromyographic amplitude during rapid eye movement sleep across the lifespan [Articolo su rivista]
Ferri, R.; Bruni, O.; Fulda, S.; Zucconi, M.; Plazzi, G.

The current definition of rapid eye movement (REM) sleep without atonia has no quantitative character, and cut-off values above which the level of electromyographic tone can be considered to be 'excessive' are unclear. The aim of this study was to analyse the characteristics of chin electromyographic amplitude by means of an automatic approach in a large group of normal controls, subdivided into different age groups. Eighty-eight normal controls were included, subdivided into six age groups: preschoolers (≤6 years); schoolers (6-10 years); preadolescents (10-13 years); young adults (24-40 years); middle-aged (58-65 years); and old (>65 years). The average amplitude of the rectified submentalis muscle electromyographic signal was used for the computation of the REM sleep Atonia Index. Chin muscle activations were detected, and their amplitude, duration and interval analysed. REM sleep Atonia Index showed a progressive and rapid increase from the preschool age to school and preadolescent age, reaching the maximum in the young adult group; after this age a small decline was observed in the middle-aged and old subjects. Conversely, the number of movements per hour in REM sleep showed a 'U'-shaped distribution across these age groups, with the minimum in the preadolescent group and the two extremes (preschool age and old) showing similar average levels of activity. Our results show that REM sleep atonia develops continuously during the lifespan, and undergoes complex changes with different developmental trajectories for REM atonia and electromyographic activations during REM sleep. Different mechanisms might subserve these two phenomena and their differential developmental dynamics.

2012 - Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome [Articolo su rivista]
Rizzo, G.; Tonon, C.; Testa, C.; Manners, D.; Vetrugno, R.; Pizza, F.; Marconi, S.; Malucelli, E.; Provini, F.; Plazzi, G.; Montagna, P.; Lodi, R.

Pathophysiology of restless legs syndrome is poorly understood. A role of the thalamus, specifically of its medial portion which is a part of the limbic system, was suggested by functional magnetic resonance imaging and positron emission tomography studies. The aim of this study was to evaluate medial thalamus metabolism and structural integrity in patients with idiopathic restless legs syndrome using a multimodal magnetic resonance approach, including proton magnetic resonance spectroscopy, diffusion tensor imaging, voxel-based morphometry and volumetric and shape analysis. Twenty-three patients and 19 healthy controls were studied in a 1.5 T system. Single voxel proton magnetic resonance spectra were acquired in the medial region of the thalamus. In diffusion tensor examination, mean diffusivity and fractional anisotropy were determined at the level of medial thalamus using regions of interest delineated to outline the same parenchyma studied by spectroscopy. Voxel-based morphometry was performed focusing the analysis on the thalamus. Thalamic volumes were obtained using FMRIB's Integrated Registration and Segmentation Tool software, and shape analysis was performed using the FMRIB Software Library tools. Proton magnetic resonance spectroscopy study disclosed a significantly reduced N-acetylaspartate:creatine ratio and N-acetylaspartate concentrations in the medial thalamus of patients with restless legs syndrome compared with healthy controls (P < 0.01 for both variable). Lower N-acetylaspartate concentrations were significantly associated with a family history of restless legs syndrome (β = -0.49; P = 0.018). On the contrary, diffusion tensor imaging, voxel-based morphometry and volumetric and shape analysis of the thalami did not show differences between the two groups. Proton magnetic resonance spectroscopic findings in patients with restless legs syndrome indicate an involvement of medial thalamic nuclei of a functional nature; however, the other structural techniques of the same region did not show any changes. These findings support the hypothesis that dysfunction of the limbic system plays a role in the pathophysiology of idiopathic restless legs syndrome.

2012 - Abnormal sleep-cardiovascular system interaction in narcolepsy with cataplexy: effects of hypocretin deficiency in humans [Articolo su rivista]
Grimaldi, D.; Calandra-Buonaura, G.; Provini, F.; Agati, P.; Pierangeli, G.; Franceschini, C.; Barletta, G.; Plazzi, G.; Montagna, P.; Cortelli, P.

STUDY OBJECTIVE: Narcolepsy with cataplexy (NC) is associated with loss of hypocretin neurons in the lateral hypothalamus involved in the circadian timing of sleep and wakefulness, and many biologic functions including autonomic control. The authors investigated whether chronic lack of hypocretin signaling alters cardiovascular control during sleep in humans. DESIGN: Comparison of 24-hr circadian rhythms, day-night, time- and state-dependent changes of blood pressure (BP) and heart rate (HR) in drug-free patients with NC and control subjects. SETTING: University hospital. PATIENTS OR PARTICIPANTS: Ten drug-free patients with NC (9 men, 1 woman) and 12 control subjects (9 men, 3 women). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Daytime BP was comparable in patients with NC and controls, but patients with NC displayed a nighttime nondipping BP pattern. The 24-hr circadian rhythmicity of BP and HR was normal in both groups. Systolic BP during nighttime rapid eye movement sleep was significantly increased in the NC group. The 24-hr HR was significantly higher in the NC group but the day-night and state-dependent HR modulations were intact. The nighttime BP pattern coupled in the NC group with increased sleep fragmentation and a higher prevalence of arousals, periodic limb movements in sleep (PLMS), and PLMS arousals. In an analysis of the sleep/cardiovascular interaction in the periods after sleep onset and preceding morning awakening, only PLMS were consistently associated with the blunted nighttime decrease in BP in the NC group. CONCLUSIONS: Hypocretin deficiency in humans may couple with an altered nighttime BP regulation that can be associated with an increased cardiovascular risk. This finding may be the result not only of the hypocretinergic deficiency per se but also of the altered sleep/wake regulation characterizing NC.

2012 - Cardiac vagal modulation and baroreflex sensitivity are reduced during wakefulness in patients with narcolepsy-cataplexy [Abstract in Rivista]
Silvani, A; Grimaldi, D; Barletta, G; Bastianini, S; Pierangeli, G; Plazzi, G; Cortelli, P

2012 - Catathrenia (sleep-related groaning) and sleep related bruxism [Capitolo/Saggio]
Plazzi, G.; Moghadam, K. K.

2012 - Catathrenia under sodium oxybate in narcolepsy with cataplexy [Articolo su rivista]
Poli, Francesca; Ricotta, L.; Vandi, Stefano; Franceschini, Christian; Pizza, Fabio; Palaia, V.; Moghadam, K. K.; Banal, D.; Vetrugno, R.; Thorpy, M. J.; Plazzi, Giuseppe

PURPOSE: This study aims to report on catathrenia occurring in narcolepsy with cataplexy (NC) patients under sodium oxybate (SO) treatment. Catathrenia is a parasomnia characterized by groaning and an abnormal respiratory pattern during sleep. METHODS: Fifty-one patients with NC and starting SO therapy underwent a baseline overnight polysomnography (PSG) to detect any sleep-related breathing disorders (SRBD). To avoid risks due to a possible central respiratory control depression by SO, all patients with concomitant obstructive sleep apnea (OSA) were treated with a nasal continuous positive airway pressure (nCPAP) device. After 2 months of treatment with SO, all patients underwent a follow-up overnight PSG to investigate possible newly occurring SRBD. They also underwent a semi-structured clinical interview to monitor other potential SO side effects. RESULTS: At baseline, four out of 51 patients showed simple snoring, and eight, mild to severe OSA. After a titration PSG night, patients with OSA received a nCPAP device. After 2 months of SO treatment, 28 patients (54.9%) showed SO-related side effects, including SRBD in 11 (21.6%). The follow-up PSG showed a respiratory pattern characteristic of catathrenia in seven patients (13.7%) as a newly observed and possibly benign SO side effect, and ruled out a worsening of OSA. CONCLUSIONS: Catathrenia should be considered a possible side effect in NC patients under SO treatment and should be accurately identified to prevent unnecessary SO withdrawal.

2012 - Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy [Articolo su rivista]
Lecendreux, M.; Bruni, O.; Franco, P.; Gringras, P.; Konofal, E.; Nevsimalova, S.; Paiva, T.; Partinen, M.; Peeters, E.; Peraita-Adrados, R.; Plazzi, G.; Poli, F.


2012 - Combined brain voxel-based morphometry and diffusion tensor imaging study in idiopathic Restless Legs Syndrome patients [Articolo su rivista]
Rizzo, G.; Manners, D.; Vetrugno, R.; Tonon, C.; Malucelli, E.; Plazzi, G.; Marconi, S.; Pizza, F.; Testa, C.; Provini, F.; Montagna, P.; Lodi, R.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the presence of abnormalities in the brain of patients with restless legs syndrome (RLS) using voxel-based morphometry and diffusion tensor imaging (DTI). METHODS: Twenty patients and twenty controls were studied. Voxel-based morphometry analysis was performed using statistical parametric mapping (SPM8) and FSL-VBM software tools. For voxel-wise analysis of DTI, tract-based spatial statistics (TBSS) and SPM8 were used. RESULTS: Applying an appropriate threshold of probability, no significant results were found either in comparison or in correlation analyses. CONCLUSIONS: Our data argue against clear structural or microstructural abnormalities in the brain of patients with idiopathic RLS, suggesting a prevalent role of functional or metabolic impairment.

2012 - Diagnostic accuracy of a structured interview for nocturnal frontal lobe epilepsy (SINFLE): a proposal for developing diagnostic criteria [Articolo su rivista]
Bisulli, Francesca; Vignatelli, L.; Naldi, Ilaria; Pittau, F.; Provini, Federica; Plazzi, Giuseppe; Stipa, C.; Leta, C.; Montagna, P.; Tinuper, Paolo

OBJECTIVES: To measure the accuracy of anamnestic features collected during clinical history for the diagnosis of nocturnal frontal lobe epilepsy (NFLE). METHODS: A case-control diagnostic study. Participants included a case group of people with ascertained target disease (NFLE group) and a control group of people with sleep disorders potentially confounding for NFLS (NOT-NFLE group), defined by means of a consensus procedure among experts (panel diagnosis as reference standard). Two major clinical patterns defining the semeiology of the epileptic event (i.e. dystonic, DP, and/or hyperkinetic pattern, HP), and 13 additional minor features were identified, formulated as questions, and telephonically administered to NFLE and NOT-NFLE groups by a trained doctor blinded to the final diagnosis. The diagnostic accuracy of each characteristic was tested against the reference standard. RESULTS: Out of 262 selected subjects, 101 were recruited; 42 were NFLE and 59 NOT-NFLE. A positive history of DP or HP had a sensitivity of 59.5% and a specificity of 91.5%, irrespective of the other minor anamnestic features. The anamnestic model improved, with a sensitivity of 59.5% and specificity of 96.6%, if at least one of the following four minor anamnestic features was added: (a) duration less than two minutes, (b) unstructured vocalization during the episode, (c) experience of an aura preceding the motor attack, and (d) a history of tonic-clonic seizures during sleep. CONCLUSIONS: The present study disclosed two major anamnestic patterns and four minor features that we called SINFLE, with unsatisfactory sensitivity but high specificity. These patterns could be the basis for developing future NFLE diagnostic criteria and to quantify the diagnostic accuracy of elements usually collected in the clinical history.

2012 - Dream enactment and violent behaviour during REM sleep: a new forensic and psychophysiological issue [Capitolo/Saggio]
Cipolli, C.; Plazzi, G.; Tuozzi, G.

Violent behaviour during an RBD episode is usually interpreted as due to an enactment of aggressive contents of dream experience in patients with neurodegenerative disease or narcolepsy with cataplexy (NC). RBD may have important forensic implications, given the potentially harmful consequences of the enacted dream for the bed-partner or the patient him/herself, but in a "noninsane" condition. Indeed, a patientl with RBD acts within the bounds of the dream and is unaware of the surroundings, and thus may not form intentions or appreciate the personal or interpersonal consequences of his/her behaviour.

2012 - Family recurrence and oligo-anuria predict uremic restless legs syndrome [Articolo su rivista]
Pizza, Fabio; Persici, Elisa; La Manna, Gaetano; Campieri, Claudio; Plazzi, Giuseppe; Carretta, Elisa; Cappuccilli, Maria; Ferri, B; Stefoni, Sergio; Montagna, P.

Objectives -  To determine clinical and laboratory predictors of restless legs syndrome (RLS) in patients with end-stage kidney disease (ESKD) undergoing long-term hemodialysis (HD). Materials and Methods -  One hundred and sixty-two consecutive patients were assessed. History of sleep disturbances, neurological examination, clinical, and laboratory data were collected. Patients with and without RLS were compared, and a logistic regression model described the relations between independent predictors and RLS. Results -  Fifty-one patients (32%) currently had RLS (RLS+). RLS+ vs RLS- patients were more frequently women (49% vs 29%, P = 0.012), had first-degree relative with RLS (22% vs 6%, P = 0.004), insomnia (59% vs 36%, P = 0.007), peripheral neuropathy (41% vs 21%, P = 0.006), and low residual diuresis (92% vs 68% with below 500 ml/24 h, P = 0.001). Low (OR = 8.71, CI = 2.27-33.41; P = 0.002) and absent (OR = 4.96, CI = 1.52-16.20; P = 0.008) residual diuresis, peripheral neuropathy (OR = 4.00, CI = 1.44-11.14; P = 0.008), and first-degree relative with RLS (OR = 3.82, CI = 1.21-12.13; P = 0.023) significantly predicted RLS in ESKD patients undergoing HD. Conclusion -  Positive family history for RLS together with reduced/absent residual renal function and peripheral neuropathy predicts the risk for RLS in ESKD patients undergoing HD. Longitudinal studies are warranted to correlate RLS occurrence with genetic and environmental factors.

2012 - Genome-wide gene expression profiling of human narcolepsy [Articolo su rivista]
Bernardini, C.; Lattanzi, W.; Bosco, P.; Franceschini, C.; Plazzi, G.; Michetti, F.; Ferri, R.

The objective of this study was to perform global gene expression profiling of patients affected by narcolepsy with cataplexy (NRLCP). This enabled identifying new potential biomarkers and relevant molecules possibly involved in the disease pathogenesis. In this study 10 NRLCP patients and 10 healthy controls were compared. Total RNA isolated from blood specimens was analyzed using microarray technology followed by statistical data analysis to detect genome-wide differential gene expression between patients and controls. Functional analysis of the gene list was performed in order to interpret the biological significance of the data. One hundred and seventy-three genes showed significant (p < 0.01) differential expression between the two tested conditions. The biological interpretation allowed categorizing differentially expressed genes involved in neurite outgrowth/extension and brain development, which could be possibly regarded as peripheral markers of the disease. Moreover, the NRLCP-related gene expression profiles indicated a dysregulation of metabolic and immune-related mechanisms. In conclusion, the gene expression profile associated to NRLCP suggested that molecular markers of neurological impairment, dysmetabolic and immune-related mechanisms, can be detected in blood of NRLCP patients.

2012 - Group I nonreciprocal inhibition in restless legs syndrome secondary to chronic renal failure [Articolo su rivista]
Marconi, S; Scaglione, C; Pizza, Fabio; Rizzo, Giovanni; Plazzi, Giuseppe; Vetrugno, R; LA MANNA, Gaetano; Campieri, Claudio; Stefoni, Sergio; Montagna, P; Martinelli, P.

BACKGROUND: Neurophysiological investigations disclosed spinal cord hyperexcitability in primary restless legs syndrome (p-RLS). Uremic RLS (u-RLS) is the most common secondary form, but its pathophysiological mechanisms remain unsettled. Aim of this study was to explore spinal cord excitability by evaluating group I nonreciprocal (Ib) inhibition in u-RLS patients in comparison with p-RLS patients and healthy subjects. METHODS: Eleven u-RLS patients undergoing long-term hemodialysis treatment, nine p-RLS patients and ten healthy subjects were studied. Soleus H reflex latency (HR-L), H(max)/M(max) ratio, and Ib inhibition were evaluated. Ib inhibition was tested measuring the amplitude changes in soleus H reflex following stimulation of the synergist gastrocnemius medialis (GM) nerve at rest. Nerve conduction studies were performed in the uremic patients. RESULTS: The H(max)/M(max) ratio did not differ in the three groups. The u-RLS patients showed a normal Ib inhibition comparable with the healthy group, whereas the p-RLS group had evidence of a reduced active inhibition compared with both u-RLS patients (P = 0.04) and controls (P = 0.007), prominently at 5 ms (P = 0.007) and at 6 ms (P = 0.02) of conditioning-test interval. Neurophysiological examination disclosed abnormalities ranging from higher HR-L to clear-cut polyneuropathy in most u-RLS patients. CONCLUSIONS: Unlike p-RLS patients, u-RLS patients had normal Ib inhibition, suggesting a regular supraspinal control of Ib spinal interneurons. Subclinical peripheral nerve abnormalities were detected in most uremic patients. Peripherally disrupted sensory modulation may represent the major pathophysiological determinant of uremic RLS.

2012 - Leg movements during wakefulness in restless legs syndrome: time structure and relationships with periodic leg movements during sleep [Articolo su rivista]
Ferri, R.; Manconi, M.; Plazzi, G.; Bruni, O.; Cosentino, F. I.; Ferini-Strambi, L.; Zucconi, M.

BACKGROUND AND OBJECTIVE: Approximately one third of patients with restless legs syndrome (RLS) also show periodic leg movements (PLM) during relaxed wake fulness (PLMW). In contrast with the large amount of data published on periodic leg movements during sleep (PLMS), PLMW have received less attention from the scientific community. The objective of this study was to evaluate the correlations/differences of time-structure and response to a dopamine-agonist between PLMW and PLMS in patients with RLS. METHODS: Ninety idiopathic RLS patients and 28 controls were recruited. Subjects underwent clinical and neurophysiological evaluation, hematological screening, and one or two consecutive full-night polysomnographic studies. A subset of patients received 0.25mg of pramipexole or placebo before the second recording. Polysomnographic recordings were scored and LM activity was analyzed during sleep and during the epochs of wakefulness occurring during the first recording hour. RESULTS: RLS patients had higher LM activity during wakefulness than controls, but with a similar periodicity. Even if correlated, the ability of the PLMW index to predict the PLMS index decreased with increasing LM activity. Intermovement intervals during wakefulness showed one peak only at approximately 4s, gradually decreasing with increasing interval in both patients and controls. The effect of pramipexole was very limited and involved the small periodic portion of LM activity during wakefulness. CONCLUSIONS: PLMW index and PLMS index were correlated; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. Short-interval LM activity during wakefulness and sleep might be linked to the severity of sleep disruption in RLS patients and the differences between their features obtained during wakefulness or sleep might be relevant for the diagnosis of sleep disturbances in RLS.

2012 - Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy [Articolo su rivista]
Heron, S. E.; Smith, K. R.; Bahlo, M.; Nobili, L.; Kahana, E.; Licchetta, L.; Oliver, K. L.; Mazarib, A.; Afawi, Z.; Korczyn, A.; Plazzi, G.; Petrou, S.; Berkovic, S. F.; Scheffer, I. E.; Dibbens, L. M.

We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.

2012 - Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy [Articolo su rivista]
Winkelmann, J.; Lin, L.; Schormair, B.; Kornum, B. R.; Faraco, J.; Plazzi, G.; Melberg, A.; Cornelio, F.; Urban, A. E.; Pizza, F.; Poli, F.; Grubert, F.; Wieland, T.; Graf, E.; Hallmayer, J.; Strom, T. M.; Mignot, E.

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30–40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy–cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD41 into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.

2012 - Periodic leg movements during sleep in narcoleptic patients with or without restless legs syndrome [Articolo su rivista]
Plazzi, G.; Ferri, R.; Franceschini, C.; Vandi, S.; Detto, S.; Pizza, F.; Poli, F.; De Cock, V. C.; Bayard, S.; Dauvilliers, Y.

We compared periodic and non-periodic leg movements during sleep and polysomnography in patients with narcolepsy with cataplexy (NC) with or without restless legs syndrome (RLS) with matched idiopathic RLS (iRLS) and control subjects. We enrolled 100 patients with NC: 17 having RLS were compared with 34 sex- and age-matched patients without RLS and with 17 normal controls and 17 iRLS subjects. Periodic leg movements were highest in iRLS and lowest in controls, with those in NC with RLS very close to iRLS, but higher than those in NC without RLS. The periodicity indexes showed the highest value in iRLS followed by NC with or without RLS and, finally, by controls. The inter-leg movement intervals peaked between 10 and 50 s in NC with RLS and in iRLS, the former did not display the nocturnal gradual decrease of periodic leg movements typical of iRLS. Periodic leg movements during sleep and polysomnography displayed specific features in RLS and NC, respectively, with NC with RLS showing an intermediate pattern. Even if RLS is only detected by targeted interview in NC, its frequency and impact on night-time sleep architecture and continuity suggest that this condition should be routinely searched for in NC.

2012 - Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy [Articolo su rivista]
Andlauer, O.; Moore H., 4th; Hong, S. C.; Dauvilliers, Y.; Kanbayashi, T.; Nishino, S.; Han, F.; Silber, M. H.; Rico, T.; Einen, M.; Kornum, B. R.; Jennum, P.; Knudsen, S.; Nevsimalova, S.; Poli, F.; Plazzi, G.; Mignot, E.

Study Objectives: To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (<= 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1. Setting: University-based sleep clinics and laboratories. Patients: Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1. Design and interventions: Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis. Measurements and Results: The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (<= 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (<= 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 +/- 0.3 versus 4.4 +/- 0.2 min) and more sleep-onset REM periods (3.6 +/- 0.1 versus 2.9 +/- 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status. Conclusion: Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy.

2012 - Sleep-dependent consolidation of motor skills in patients with narcolepsy-cataplexy [Articolo su rivista]
Mazzetti, M.; Plazzi, G.; Campi, C.; Cicchella, A.; Mattarozzi, K.; Tuozzi, G.; Vandi, S.; Vignatelli, L.; Cipolli, C.

Background and Objectives: This study investigated whether the altered organization of post-training sleep in patients with narcolepsy-cataplexy (NC) is associated with a lower off-line improvement in the consolidation of motor skills compared with normal subjects. Study Design: Fourteen drug-naive NC patients, fulfilling the international clinical and polysomnographic diagnostic criteria, and 14 individually-matched controls underwent training at a sequential finger tapping task (FTT) and were re-tested on the next morning (after a night with polysomnographic recording) and after another six nights (spent at home). Setting: Training and retrieval sessions were performed in a controlled laboratory setting. Results: FTT performance was worse in NC patients than controls at training and at both retrieval sessions and showed a fairly different time course (slower than in controls) of consolidation. Several sleep indices (lower values of stage-2 NREM sleep and SWS) were compatible with a lower effectiveness of sleep for consolidation of motor skills in NC patients, although no statistically significant relationship was found between such indices and improvement rate. Conclusion: The consolidation process of motor skills results less effective in NC patients since training and slower than in normal subjects over the week following training. The wider variations in performance scores and sleep parameters of post.-training night in NC patients relative to controls suggest that a) the lower initial consolidation may be due to a less effective encoding consequent to altered prior sleep, and b) the consolidation process over the 24 h following training is negatively influenced not only by the altered characteristics of post-training sleep, but also by the daytime sleepiness following training.

2012 - The burden of narcolepsy with cataplexy: How disease history and clinical features influence socio-economic outcomes [Articolo su rivista]
Ingravallo, F.; Gnucci, V.; Pizza, F.; Vignatelli, L.; Govi, A.; Dormi, A.; Pelotti, S.; Cicognani, A.; Dauvillers, Y.; Plazzi, G.

Objective: To investigate in narcolepsy with cataplexy (NC) patients of working age (18–65 years) the influence of age at onset, age at diagnosis and clinical features on socio-occupational conditions, disease- related economic burden, and quality of life. Methods: One hundred consecutive patients underwent a semistructured interview on socio-occupational aspects, NC-related direct and indirect costs, and NC history. Questionnaires were used to evaluate excessive daytime sleepiness, cataplexy, depressive symptoms, and quality of life. Results: NC patients (51 males, mean age 37 ± 11.5 years) had educational and occupational levels similar to those of the Italian population of the same age range, but married less often, especially if NC onset occurred at a young age. Total annual NC-related costs were €9814 ± 10,372 per patient. Multivariate analyses showed that patients with NC onset before the age of 30 years had a higher educational level, married less frequently, and were less frequently unemployed or inactive (retired, housewife). Patients diagnosed before the age of 30 years were less frequently unemployed or inactive, had fewer work changes, and had a better general health perception. Irresistible sleepiness was associated with work absences and higher indirect costs. Depressive symptoms were strongly associated with lower qualityof- life scores. Conclusions: NC age at onset and at diagnosis modulates the disease-related burden. A diagnosis at a young age could improve patients’ occupational prognosis, and their general health perception.

2012 - The distinct movement disorder in anti-N-methyl-D-aspartate-receptor encephalitis may be related to status dissociatus: A hypothesis [Articolo su rivista]
Stamelou, M.; Plazzi, G.; Lugaresi, E.; Edwards, M. J.; Bhatia, K. P.

The majority of patients with anti-N-methyl-D-aspartate-receptor encephalitis (NMDAE) present a characteristic movement disorder, which consists of complex bilateral stereotyped movements of the arms, with perioral and eye movements, and less frequently involvement of the legs. We have observed striking similarities in the characteristics of the abnormal movements observed in NMDAE and those described in Status Dissociatus, which is characterized by a complete breakdown of state-determining boundaries (wakefulness, REM and NREM sleep) and can result from pathophysiologically diverse disorders (e.g. fatal familial insomnia, delirium tremens, Morvan's syndrome). Here, we suggest that the state of paradoxical responsiveness in which NMDAE patients present these stereotyped movements may be that of Status Dissociatus and discuss the clinical similarities and pathophysiological explanations that support such a suggestion. This hypothesis explains why patients that seem to be unconscious have a movement disorder that is not epileptic and may have management implications, since many patients with NMDAE-related movement disorder are treated with anticonvulsants that may not be indicated.

2012 - The importance to assess the true "periodicity" of leg movements during sleep in narcolepsy [Articolo su rivista]
Ferri, R.; Bruni, O.; Zucconi, M.; Plazzi, G.


2012 - Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study [Articolo su rivista]
Lecendreux, M.; Poli, F.; Oudiette, D.; Benazzouz, F.; Donjacour, C. E.; Franceschini, C.; Finotti, E.; Pizza, F.; Bruni, O.; Plazzi, G.

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy.

2011 - A 5-year prospective cohort study on health-related quality of life in patients with narcolepsy [Articolo su rivista]
Vignatelli, L.; Plazzi, Giuseppe; Peschechera, F.; Delaj, L.; D'Alessandro, Roberto

OBJECTIVE: To evaluate the 5-year variation of health-related quality of life (HRQoL) and mood symptoms in a cohort of patients with narcolepsy. METHODS: Adults attending the Sleep Centre of the Department of Neurological Sciences, University of Bologna in 1997 and meeting the International Classification of Sleep Disorders-Revised criteria for the diagnosis of narcolepsy were eligible. Included patients self-administered the Medical Outcome Short Form-36 (SF-36) and the Zung depression scale (ZDS) prospectively in 1998 and 2003. RESULTS: There was no significant difference between 1998 and 2003 measures of SF-36 and ZDS in the 54 patients included. About 25% of them showed moderate or severe mood symptoms in both observations. ZDS score (inversely) and duration of disease (directly) explained a percentage of variance of role physical, vitality (VT), social functioning (SF) and role emotional. At the second observation VT and SF had a further percentage of variance explained by excessive daytime sleepiness (EDS) and age at onset. Self-reported diabetes frequency doubled after 5 years (from 7% to 17%). CONCLUSIONS: Patients with narcolepsy show a stable impairment of HRQoL in a 5-year period with respect to Italian normative data. Mood status and EDS negatively influence their HRQoL while disease duration has a positive influence.

2011 - Autonomic disturbances in narcolepsy [Articolo su rivista]
Plazzi, Giuseppe; Moghadam, K. K.; Maggi, L. S.; Donadio, V.; Vetrugno, R.; Liguori, Rocco; Zoccoli, Giovanna; Poli, F.; Pizza, Fabio; Pagotto, Uberto; Ferri, R.

Narcolepsy is a clinical condition characterized mainly by excessive sleepiness and cataplexy. Hypnagogic hallucinations and sleep paralysis complete the narcoleptic tetrad; disrupted night sleep, automatic behaviors and weight gain are also usual complaints. Different studies focus on autonomic changes or dysfunctions among narcoleptic patients, such as pupillary abnormalities, fainting spells, erectile dysfunction, night sweats, gastric problems, low body temperature, systemic hypotension, dry mouth, heart palpitations, headache and extremities dysthermia. Even if many studies lack sufficient standardization or their results have not been replicated, a non-secondary involvement of the autonomic nervous system in narcolepsy is strongly suggested, mainly by metabolic and cardiovascular findings. Furthermore, the recent discovery of a high risk for overweight and for metabolic syndrome in narcoleptic patients represents an important warning for clinicians in order to monitor and follow them up for their autonomic functions. We review here studies on autonomic functions and clinical disturbances in narcoleptic patients, trying to shed light on the possible contribute of alterations of the hypocretin system in autonomic pathophysiology.

2011 - Cognitive evoked potentials in narcolepsy: A review of the literature [Articolo su rivista]
Raggi, A.; Plazzi, Giuseppe; Pennisi, G.; Tasca, D.; Ferri, R.

Subtle cognitive deficits have been described in narcolepsy. They have been hypothesised to be related to changes in the hypocretin system. Event-related potential (ERP) paradigms are known to be useful tools in the investigation of information processing and seem to be sensitive to subtle neuropsychological changes. We review empirical articles on ERPs in narcolepsy in order to contribute to clarify the pattern of cognitive deficits that are specific to this disease and, possibly, to identify specific cognitive domains that improve with treatment. Fourteen peer-reviewed articles were selected for this review. These studies were conducted with passive and active oddball paradigms and support the existence of changes in cognitive attentive processing in narcolepsy, possibly in association with altered functioning of the prefrontal cortex. ERP low-resolution electromagnetic tomography revealed that modafinil improved information processing speed and increased energetic resources in prefrontal cortical areas. These findings suggest that it is worthwhile to further evaluate the usefulness of ERPs in the detection of cognitive dysfunction in this disorder before and after treatment.

2011 - Common variants in P2RY11 are associated with narcolepsy [Articolo su rivista]
Kornum, B. R.; Kawashima, M.; Faraco, J.; Lin, L.; Rico, T. J.; Hesselson, S.; Axtell, R. C.; Kuipers, H.; Weiner, K.; Hamacher, A.; Kassack, M. U.; Han, F.; Knudsen, S.; Li, J.; Dong, X.; Winkelmann, J.; Plazzi, G.; Nevsimalova, S.; Hong, S. C.; Honda, Y.; Honda, M.; Hogl, B.; Ton, T. G.; Montplaisir, J.; Bourgin, P.; Kemlink, D.; Huang, Y. S.; Warby, S.; Einen, M.; Eshragh, J. L.; Miyagawa, T.; Desautels, A.; Ruppert, E.; Hesla, P. E.; Poli, F.; Pizza, F.; Frauscher, B.; Jeong, J. H.; Lee, S. P.; Strohl, K. P.; Longstreth, W. T. Jr.; Kvale, M.; Dobrovolna, M.; Ohayon, M. M.; Nepom, G. T.; Wichmann, H. E.; Rouleau, G. A.; Gieger, C.; Levinson, D. F.; Gejman, P. V.; Meitinger, T.; Peppard, P.; Young, T.; Jennum, P.; Steinman, L.; Tokunaga, K.; Kwok, P. Y.; Risch, N.; Hallmayer, J.; Mognot, E.

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

2011 - Complex movement disorders at disease onset in childhood narcolepsy with cataplexy [Articolo su rivista]
Plazzi, G.; Pizza, F.; Palaia, V.; Franceschini, C.; Poli, F.; Moghadam, K. K.; Cortelli, P.; Nobili, L.; Bruni, O.; Dauvilliers, Y.; Lin, L.; Edwards, M. J.; Mignot, E.; Bhatia, K. P.

Narcolepsy with cataplexy is characterized by daytime sleepiness, cataplexy (sudden loss of bilateral muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. Narcolepsy with cataplexy is most often associated with human leucocyte antigen-DQB1*0602 and is caused by the loss of hypocretin-producing neurons in the hypothalamus of likely autoimmune aetiology. Noting that children with narcolepsy often display complex abnormal motor behaviours close to disease onset that do not meet the classical definition of cataplexy, we systematically analysed motor features in 39 children with narcolepsy with cataplexy in comparison with 25 age- and sex-matched healthy controls. We found that patients with narcolepsy with cataplexy displayed a complex array of 'negative' (hypotonia) and 'active' (ranging from perioral movements to dyskinetic-dystonic movements or stereotypies) motor disturbances. 'Active' and 'negative' motor scores correlated positively with the presence of hypotonic features at neurological examination and negatively with disease duration, whereas 'negative' motor scores also correlated negatively with age at disease onset. These observations suggest that paediatric narcolepsy with cataplexy often co-occurs with a complex movement disorder at disease onset, a phenomenon that may vanish later in the course of the disease. Further studies are warranted to assess clinical course and whether the associated movement disorder is also caused by hypocretin deficiency or by additional neurochemical abnormalities.

2011 - Different sleep onset criteria at the multiple sleep latency test (MSLT): an additional marker to differentiate central nervous system (CNS) hypersomnias [Articolo su rivista]
Pizza, Fabio; Vandi, Stefano; Detto, S.; Poli, F.; Franceschini, C.; Montagna, P.; Plazzi, Giuseppe

Excessive daytime sleepiness (EDS) has different correlates in non-rapid eye movement (NREM) [idiopathic hypersomnia (IH) without long sleep time] and REM sleep [narcolepsy without cataplexy (NwoC) and narcolepsy with cataplexy (NC)]-related hypersomnias of central origin. We analysed sleep onset characteristics at the multiple sleep latency test (MSLT) applying simultaneously two sleep onset criteria in 44 NC, seven NwoC and 16 IH consecutive patients referred for subjective EDS complaint. Sleep latency (SL) at MSLT was assessed both as the time elapsed to the occurrence of a single epoch of sleep Stage 1 NREM (SL) and of unequivocal sleep [three sleep Stage 1 NREM epochs or any other sleep stage epoch, sustained SL (SusSL)]. Idiopathic hypersomnia patients showed significantly (P<0.0001) longer SusSL than SL (7.7±2.5 versus 5.6±1.3 min, respectively) compared to NwoC (5.8±2.5 versus 5.3±2.2 min) and NC patients (4.1±3 versus 3.9±3 min). A mean difference threshold between SusSL and SL ≥27 s reached a diagnostic value to discriminate IH versus NC and NwoC sufferers (sensitivity 88%; specificity 82%). Moreover, NC patients showed better subjective sleepiness perception than NwoC and IH cases in the comparison between naps with or without sleep occurrence. Simultaneous application of the two widely used sleep onset criteria differentiates IH further from NC and NwoC patients: IH fluctuate through a wake-Stage 1 NREM sleep state before the onset of sustained sleep, while NC and NwoC shift abruptly into a sustained sleep. The combination of SusSL and SL determination at MSLT should be tested as an additional objective differential criterion for EDS disorders.

2011 - Erratum: Common variants in P2RY11 are associated with narcolepsy (Nature Genetics (2011) 43 (66-71)) [Articolo su rivista]
Kornum, B. R.; Kawashima, M.; Faraco, J.; Lin, L.; Rico, T. J.; Hesselson, S.; Axtell, R. C.; Kuipers, H.; Weiner, K.; Hamacher, A.; Kassack, M. U.; Han, F.; Knudsen, S.; Li, J.; Dong, X.; Winkelmann, J.; Plazzi, G.; Nevsimalova, S.; Hong, S. -C.; Honda, Y.; Honda, M.; Hogl, B.; Ton, T. G. N.; Montplaisir, J.; Bourgin, P.; Kemlink, D.; Huang, Y. -S.; Warby, S.; Einen, M.; Eshragh, J. L.; Miyagawa, T.; Desautels, A.; Ruppert, E.; Hesla, P. E.; Poli, F.; Pizza, F.; Frauscher, B.; Jeong, J. -H.; Lee, S. -P.; Strohl, K. P.; Longstreth, W. T.; Kvale, M.; Dobrovolna, M.; Ohayon, M. M.; Nepom, G. T.; Wichmann, H. -E.; Rouleau, G. A.; Gieger, C.; Levinson, D. F.; Gejman, P. V.; Meitinger, T.; Peppard, P.; Young, T.; Jennum, P.; Steinman, L.; Tokunaga, K.; Kwok, P. -Y.; Risch, N.; Hallmayer, J.; Mignot, E.

2011 - High pain frequency in narcolepsy with cataplexy [Articolo su rivista]
Dauvilliers, Y.; Bayard, S.; Shneerson, J. M.; Plazzi, Giuseppe; Myers, A. J.; Garcia Borreguero, D.

BACKGROUND: Narcolepsy with cataplexy (NC) is caused by the loss of hypocretin neurons. Recent studies highlighted the roles for hypocretins in the modulation of nociceptive transmission. The aims of the present multicenter case-control study were to look at the frequency of pain in NC and to study the determinants and impact of pain on narcolepsy symptoms and quality of life (QoL). METHODS: Sixty-seven adult patients with NC, together with their physician, partner/friend, and sex- and age-matched normal controls underwent a face-to-face interview and completed questionnaires on the presence and frequency of pain, narcolepsy symptoms and QoL (Short-Form 36-item score, Functional Outcomes of Sleep Questionnaire, Medical Outcomes Study, Fatigue Severity Scale, and Beck Depression Inventory). RESULTS: One-third (32.8%) of NC patients experienced pain at least monthly, with a significantly higher frequency and impact than controls (17.9%) and independent of the patients' narcolepsy medication. The reporting of pain was well matched between patients and partners/friends but significant differences were observed between patients and physicians, with physicians significantly underestimating its frequency and impact. The location of chronic pain varies within subjects with differences between NC and controls. We pinpointed that sleep quantity and depression were determinants for pain, and chronic pain had significant impact on sleep quantity, depression and QoL in NC. CONCLUSION: We report, for the first time, evidence that chronic pain is significantly more common and disabling in NC compared to the general population. The findings call for improved attention to assessment and treatment of pain in the follow-up of NC.

2011 - L'analisi dell'accordo fra osservatori e delle fonti di variabilità come strumento per il miglioramento della qualità in medicina legale [Relazione in Atti di Convegno]
Ingravallo, F.; Vignatelli, L.; Plazzi, G.; Cicognani, A.

2011 - Linee guida per l’accertamento dell’idoneità alla guida in soggetti affetti da Sindrome delle apnee ostruttive del sonno (OSAS) e Narcolessia. [Guidelines for the fitness to drive assessment in people with obstructive sleep apnoea syndrome (OSAS) and narcolepsy] [Articolo su rivista]
Garbarino, S.; Bonanni, E.; Ingravallo, F.; Mondini, S.; Plazzi, G.; Sanna, A.

Given the prevalence of sleep disorders and sleep deprivation in modern societies, and the correlation between sleepiness and work and driving accidents, the excessive daytime sleepiness is an important issue. Although many studies showed that patients with untreated Obstructive sleep apnoea syndrome (OSAS) and narcolepsy have an higher risk for driving accidents, neither the European Community regulation nor the Italian law of the driving licence mention restrictions for these disorders. In 2010 the scientific association COMLAS (Association of legal medicine professionals of the Italian National Health Service) published the Guidelines for the examination by the Local Medical Commissions. The author presented the guidelines to assess the fitness to drive of people with OSAS or narcolepsy. The proposed criteria, set up in collaboration with the Commission "Sleepiness, Safety and Transportation" of the Italian Association of Sleep Medicine (AIMS), can be considered among the most advanced internationally

2011 - Motor events during REM sleep in patients with narcolepsy-cataplexy: a video-polysomnographic pilot study [Articolo su rivista]
Franceschini, C.; Ferri, R.; Pizza, Fabio; Ricotta, L.; Vandi, Stefano; Detto, S.; Poli, Francesca; Pruneti, C.; Mazzetti, Michela; Cipolli, Carlo; Lugaresi, E.; Plazzi, Giuseppe

Objective: To investigate in narcolepsy with cataplexy (NC) patients of working age (18-65 years) the influence of age at onset, age at diagnosis and clinical features on socio-occupational conditions, disease-related economic burden, and quality of life. Methods: One hundred consecutive patients underwent a semistructured interview on socio-occupational aspects, NC-related direct and indirect costs, and NC history. Questionnaires were used to evaluate excessive daytime sleepiness, cataplexy, depressive symptoms, and quality of life. Results: NC patients (51 males, mean age 37 +/- 11.5 years) had educational and occupational levels similar to those of the Italian population of the same age range, but married less often, especially if NC onset occurred at a young age. Total annual NC-related costs were (sic)9814 +/- 10,372 per patient. Multivariate analyses showed that patients with NC onset before the age of 30 years had a higher educational level, married less frequently, and were less frequently unemployed or inactive (retired, housewife). Patients diagnosed before the age of 30 years were less frequently unemployed or inactive, had fewer work changes, and had a better general health perception. Irresistible sleepiness was associated with work absences and higher indirect costs. Depressive symptoms were strongly associated with lower quality-of-life scores. Conclusions: NC age at onset and at diagnosis modulates the disease-related burden. A diagnosis at a young age could improve patients' occupational prognosis, and their general health perception.

2011 - Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study [Articolo su rivista]
Palaia, V.; Poli, F.; Pizza, F.; Antelmi, E.; Franceschini, C.; Moghadam, K. K.; Provini, F.; Pagotto, U.; Montagna, P.; Schenck, C. H.; Mignot, E.; Plazzi, G.

STUDY OBJECTIVES: To assess the prevalence of sleep related-eating disorder (SRED) and nocturnal smoking (NS) in patients with narcolepsy with cataplexy (NC). DESIGN: Case-control study. SETTING: University hospital. PATIENTS OR PARTICIPANTS: 65 consecutive adult NC patients (33 men; mean age 43.9 ± 19.2 years) and 65 age-, sex-, and geographical origin-matched controls. INTERVENTIONS: Validated questionnaires were used to investigate SRED, NS, restless legs syndrome (RLS), and psychopathological traits (using Eating Disorder Inventory-2 [EDI-2]; Maudsley Obsessive-Compulsive Inventory [MOCI]; and Beck Depression Inventory [BDI]). MEASUREMENTS AND RESULTS: NC patients showed a higher prevalence of SRED (32% vs 3%, P=0.00001), NS (21% vs 0%, P=0.00006), and RLS (18% vs 5%, P=0.013) than controls. Moreover, NC patients presented more frequently with an eating-related pathological profile on the EDI-2 (80% vs 46%, P=0.00006) and had a higher prevalence of depressed mood on the BDI (41% vs 18%, P=0.004). In comparison to patients without SRED, NC patients with SRED were more frequently women (71% vs 39%, P=0.013), had higher "bulimic" (29% vs 2%, P=0.004) and "social insecurity" (48% vs 18%, P=0.013) traits on the EDI-2, had higher obsessive-compulsiveness on the MOCI (29% vs 4%, P = 0.009), and were more depressed on the BDI (67% vs 29%, P=0.005). NC patients with NS showed more frequent pathological profiles on the EDI-2 (100% vs 75%, P=0.035), including the "bulimic" (29% vs 6%, P=0.015), "perfectionism" (43% vs 14%, P=0.016), and "social insecurity" (50% vs 22, P=0.035) profiles. CONCLUSION: Our study shows a strong association of the compulsive nocturnal behaviors SRED and NS with adult NC.

2011 - Overnight distribution and motor characteristics of REM sleep behaviour disorder episodes in patients with narcolepsy-cataplexy [Articolo su rivista]
Cipolli, C.; Franceschini, C.; Mattarozzi, K.; Mazzetti, M.; Plazzi, G.

OBJECTIVE: The study aimed to examine the temporal distribution of episodes of REM sleep behaviour disorder (RBD) over the night and their motor and polysomnographic (PSG) characteristics in patients with narcolepsy-cataplexy (NC). METHODS: Full-night video-PSG recordings of a continuous series of 37 drug-naïve NC patients with clinically-documented RBD were examined to detect the occurrences of RBD episodes (disclosed in 27 patients) and to classify their related PSG and motor behaviour features. RESULTS: RBD episodes occurred with comparable frequency in REM sleep periods of the first and second halves of the night, regardless of the length of REM periods, patients' age or disease duration. Vocalisations and pantomimes occurred in comparable proportions of RBD episodes in the two halves of the night, while aggressive-violent movements were significantly more frequent in RBD episodes of the second half of the night. No sleep parameter significantly differed in patients with RBD occurring in the first/second/neither half of the night. CONCLUSIONS: RBD episodes (a) are not an every night phenomenon in NC patients with clinically documented RBD, regardless of their age or disease duration; (b) can occur in any period of REM sleep, regardless of length; and (c) display less violent-aggressive motor features when they occur in the first half of the night. Multi-night studies with dream-report collection may disclose whether this overnight variation in the violent-aggressive features in RBD episodes of NC patients is associated with a time-of-night-related variation in dream content.

2011 - Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment [Articolo su rivista]
LA MANNA, Gaetano; Pizza, Fabio; Persici, Elisa; Baraldi, Olga; Comai, Giorgia; Cappuccilli, Maria; Centofanti, Francesca; Carretta, Elisa; Plazzi, Giuseppe; Colì, L; Montagna, P; Stefoni, Sergio

BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterized by paraesthesia, dysaesthesia and the irresistible urge to move the legs especially at night. Its prevalence is much higher among dialysis patients at 12 to 62% compared to 3 to 9% in the general population. Here, we investigated the association between RLS and cardiovascular events risk and laboratory parameters in end-stage kidney disease (ESKD) patients on dialysis. METHODS: One hundred ESKD patients undergoing haemodialysis were enrolled in an 18-month prospective observational study. The main outcomes were the associations of RLS with new cardiovascular events and cardiovascular mortality. RESULTS: RLS affected 31% of the study population. It was associated with female gender, gradual reduction in residual diuresis, lower albumin (P = 0.039) and inflammation, but not the dialysis parameters Kt/V and URR. During observation, 47% of patients experienced new cardiovascular events (64.5% with and 39.1% without RLS; P = 0.019). New cardiovascular events increased with severity of RLS [intermittent (I-RLS) vs continuous (C-RLS)]. Mortality was 20.0% in all patients, 32.3% in those with and 14.5% in patients without RLS (P = 0.04). In patients with I-RLS, mortality was 23.8% compared to 55.6% in patients with C-RLS (P = 0.014). Multivariate analysis confirmed the relationship between RLS and mortality. CONCLUSIONS: This study confirmed the high prevalence of RLS among dialysis patients and the associations between the severity of RLS and the risk of new cardiovascular events and higher short-term mortality.

2010 - Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy [Articolo su rivista]
Kawashima, M.; Lin, L.; Tanaka, S.; Jennum, P.; Knudsen, S.; Nevsimalova, S.; Plazzi, G.; Mignot, E.

2010 - Behavioural and neurophysiological correlates of human cataplexy: a video-polygraphic study [Articolo su rivista]
Vetrugno, R.; D'Angelo, R.; Moghadam, K. K.; Vandi, Stefano; Franceschini, Christian; Mignot, E.; Montagna, Pasquale; Plazzi, Giuseppe

2010 - Catathrenia (sleep related groaning) [Capitolo/Saggio]
R., Vetrugno; Plazzi, Giuseppe; P., Montagna

Sleep related groaning was first reported in the medical literature in 1983 when De Roeck and Van Hoof described, in abstract form, the case of a young male with groaning during REM sleep as the result of forced and prolonged expiration.

2010 - Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children [Articolo su rivista]
Aran, A.; Einen, M.; Lin, L.; Plazzi, G.; Nishino, S.; Mignot, E.

Study Objective: To report on symptoms and therapies used in childhood narcolepsy-cataplexy. Design, Patients, and Setting: Retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire. Measurements and Results: Patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated "off label" with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs. Conclusion: This study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.

2010 - Diurnal and nocturnal sleep in narcolepsy with cataplexy [Capitolo/Saggio]
Dauvilliers, Y.; Plazzi, G.

Narcolepsy is an under-recognized disease, but classically reported as one of the most severe conditions of chronic hypersomnia. Excessive daytime sleepiness is usually the first symptom to appear in childhood or in young adulthood, occurring daily, often irresistible, with short duration, capable of restoring normal vigilance for one to several hours, and associated with dreaming. In contrast, disturbed nocturnal sleep is clearly underestimated in that condition and, even if not included in diagnostic criteria, this complaint may be considered as the fifth component in addition to the narcolepsy tetrad. The presence of poor sleep at night may represent a significant and severe symptom in patients, especially with the evolution process. The diagnosis of narcolepsy with cataplexy is essentially clinical, but requires, whenever possible, a nocturnal PSG recording followed by an MSLT showing short mean sleep latencies and the presence of sleep-onset REM (REM) periods. Typically, the nighttime sleep of narcoleptics is highly fragmented with several long awakenings that may be associated with dissociated sleep/wake states, abnormal movements or behaviours during REM or non-REM (NREM) sleep, periodic leg movements during wakefulness and sleep, and sleep-disorder breathing. All narcolepsy symptoms and associated conditions need to be considered in the management of the disorder, but daytime sleepiness in narcolepsy seems independent of the amount and quality of nighttime sleep. © 2010 Springer-Verlag New York.

2010 - Hypocretin deficiency in narcolepsy with cataplexy is associated with a normal body core temperature modulation [Articolo su rivista]
Grimaldi, Daniela; Agati, Patrizia; Pierangeli, Giulia; Franceschini, Christian; Guaraldi, Pietro; Barletta, Giorgio; Vandi, Stefano; Cevoli, S.; Plazzi, Giuseppe; Montagna, Pasquale; Cortelli, Pietro

2010 - Improved computation of the atonia index in normal controls and patients with REM sleep behavior disorder [Articolo su rivista]
Ferri, R.; Rundo, F.; Manconi, M.; Plazzi, G.; Bruni, O.; Oldani, A.; Ferini-Strambi, L.; Zucconi, M.

2010 - Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: a common mechanism? [Articolo su rivista]
Bisulli, F.; Vignatelli, L.; Naldi, I.; Licchetta, L.; Provini, F.; Plazzi, G.; Di Vito, L.; Ferioli, S.; Montagna, P.; Tinuper, P.

2010 - Increased prevalence of nocturnal smoking in restless legs syndrome (RLS) [Articolo su rivista]
Provini, F.; Antelmi, E.; Vignatelli, L.; Zaniboni, A.; Naldi, G.; Calandra-Buonaura, G.; Vetrugno, R.; Plazzi, G.; Pizza, F.; Montagna, P.

2010 - Injurious REM sleep behaviour disorder in narcolepsy with cataplexy contributing to criminal proceedings and divorce [Articolo su rivista]
Ingravallo, F.; Schenck, C. H.; Plazzi, G.

2010 - Insomnia cycling with a 42-day infradian period: evidence for two uncoupled circadian oscillators? [Articolo su rivista]
Vignatelli, L.; Masetti, S.; Amore, M.; Laterza, C.; Mattarozzi, K.; Pierangeli, G.; Cortelli, P.; Vandi, S.; Vetrugno, R.; Plazzi, G.; Montagna, P.

2010 - Medico-Legal Aspects of Disability in Narcolepsy [Capitolo/Saggio]
Ingravallo, F.; Plazzi, G.

Narcolepsy is a severe, chronic, disabling disease affecting almost all personal and social activities. The detrimental effect of narcolepsy on patients’ working lives may be severe and long-lasting, but the impairment due to narcolepsy varies widely. Disability assessment is complex because of the lack of objective measures to assess and quantify excessive daytime sleepiness, which is considered to be the main disabling symptom of narcolepsy. This chapter considers the medical aspects of work disability in narcolepsy, and the essential issues clinicians and researchers have to address in providing medical information to assist determination of disability in people with narcolepsy. In conclusion, a work disability classification of narcolepsy is proposed.

2010 - Narcolepsy with cataplexy associated with holoprosencephaly misdiagnosed as epileptic drop attacks [Articolo su rivista]
Plazzi, G; Tonon, C; Rubboli, G; Poli, F; Franceschini, C; Pizza, F; Bisulli, A; Rizzo, G; Mignot, E; Montagna, P; Lodi, R

2010 - Narcolepsy with cataplexy associated with holoprosencephaly misdiagnosed as epileptic drop attacks (Movement Disorders (2010) 25, 6, (788-790)) [Articolo su rivista]
Plazzi, Giuseppe; Tonon, Caterina; Rubboli, G.; Poli, Francesca; Franceschini, Christian; Pizza, Fabio; Bisulli, Antonietta; Rizzo, Giovanni; Mignot, E.; Montagna, Pasquale; Lodi, Raffaele

2010 - Olfactory dysfunction in narcolepsy with cataplexy [Articolo su rivista]
Bayard, S.; Plazzi, G.; Poli, F.; Serra, L.; Ferri, R.; Dauvilliers, Y.

2010 - Preface [Capitolo/Saggio]
Thorpy, M. J.; Plazzi, G.

Intense medical and scientific interest in an increasing number of topics in sleep medicine has led to the production of this volume on Parasomnias and Other Sleep-Related Movement Disorders. Although parasomnias are ubiquitous in childhood and occur across all ages, this is the first publication to focus on this topic in detail. There is growing recognition that sleep disorders represent a major public health concern, and understanding the basic, translational, clinical and psychosocial aspects of sleep disorders is essential to the process of becoming a skilled clinical practitioner. The earliest reported descriptions of some of the parasomnias such as sleepwalking and nightmares have been known since antiquity; however, new parasomnias have been described, such as REM sleep behavior disorder and catathrenia. There have been numerous developments in the field of abnormal movement disorders during sleep that have led to a better understanding of the clinical features, the diagnostic criteria and subsequently, treatments. These developments have continually deepened our understanding of parasomnias as pathophysiological conditions and have also drawn attention to the impact on the lives of those who have these conditions. Parasomnias can be severe, chronic, debilitating and disabling neurological disorders, often having early age of onset. They frequently involve abnormal involuntary behaviors during sleep, leading to injuries, emotional distress and even medico-legal liability. Despite their prominent symptoms and impact on patients' health-related quality of life, parasomnias remain under-recognized and under-appreciated disorders, perhaps because of their predominantly night-time occurrence.

2010 - Propriospinal myoclonus [Capitolo/Saggio]
Plazzi, Giuseppe; R., Vetrugno

The term myoclonus was derived from the longer term "paramyoklonus multiplex" that was first used in a case report by professor Nikolaus Friedreich in Heidelberg in 1881 with the intent to describe symmetric (para) an quick (clonus) movement of muscles (myo) occurring in multiple sites (multiplex) over the body.

2010 - Pseudocataplexy in narcolepsy with cataplexy [Articolo su rivista]
Plazzi, G.; Khatami, R.; Serra, L.; Pizza, F.; Bassetti, C. L.

2010 - REM sleep behavior disorder in narcolepsy with cataplexy [Capitolo/Saggio]
Plazzi, G.; Dauvilliers, Y.

Narcolepsy with cataplexy (NC) is a chronic disease characterized by excessive daytime sleepiness, striking transitions from wakefulness into rapid eye movement (REM) sleep, typically associated with cataplexy and other phenomena due to the abnormal occurrence of REM sleep elements during wakefulness (sleep paralysis and hallucinations) and frequent sleep/wake transitions. Nocturnal sleep in NC is usually disturbed by a large cohort of phenomena: vivid frightening dreams, several nocturnal awakenings, REM sleep behavior disorder (RBD), periodic leg movement (PLM), obstructive sleep apnea (OSA), sleep-related eating disorders and other parasomnias. Several clinical and polysomnographic aspects seem to differentiate RBD in patients with narcolepsy from idiopathic or secondary RBD, suggesting the involvement of specific neurophysiological, neurochemical and neuropathological substrates. © 2010 Springer-Verlag New York.

2010 - REM-dreams recall in patients with narcolepsy-cataplexy [Articolo su rivista]
Mazzetti, M.; Bellucci, C.; Mattarozzi, K.; Plazzi, G.; Tuozzi, G.; Cipolli, C.

2010 - Restless legs syndrome is frequent in narcolepsy with cataplexy patients [Articolo su rivista]
Plazzi, Giuseppe; Ferri, R.; Antelmi, Elena; Bayard, S.; Franceschini, Christian; Cosentino, F. I.; Abril, B.; Spruyt, K.; Provini, Federica; Montagna, Pasquale; Dauvilliers, Y.

2010 - Rhythmic movements and sleep paralysis in narcolepsy with cataplexy: a video-polygraphic study [Articolo su rivista]
Pizza, Fabio; Moghadam, K. K.; Franceschini, Christian; Bisulli, Antonietta; Poli, Francesca; Ricotta, L.; Vetrugno, R.; Vandi, Stefano; Montagna, Pasquale; Plazzi, Giuseppe

2010 - Sodium oxybate is an effective and safe treatment for narcolepsy [Articolo su rivista]
Lammers, G. J.; Bassetti, C.; Billiard, M.; Black, J.; Broughton, R.; Dauvilliers, Y.; Ferini Strambi, L.; Garcia-Borreguero, D.; Goswami, M.; Hogl, B.; Iranzo, A.; Jennum, P.; Khatami, R.; Lecendreux, M.; Mayer, G.; Mignot, E.; Montplaisir, J.; Nevsimalova, S.; Peraita-Adrados, R.; Plazzi, G.; Scammell, T.; Silber, M.; Sonka, K.; Tafti, M.; Thorpy, M.

2010 - Spectral analysis of heart rate variability reveals an enhanced sympathetic activity in narcolepsy with cataplexy [Articolo su rivista]
Grimaldi, Daniela; Pierangeli, Giulia; Barletta, Giorgio; Terlizzi, Rossana; Plazzi, Giuseppe; Cevoli, S.; Franceschini, Christian; Montagna, Pasquale; Cortelli, Pietro

2010 - Surgery vs ventilation in adult severe obstructive sleep apnea syndrome [Articolo su rivista]
Vicini, C.; Dallan, I.; Campanini, A.; De Vito, A.; Barbanti, F.; Giorgiomarrano, G.; Bosi, M.; Plazzi, G.; Provini, F.; Lugaresi, E.

2010 - The Parasomnias and other sleep-related movement disorders [Monografia/Trattato scientifico]
Thorpy, M. J.; Plazzi, Giuseppe

Although parasomnias are ubiquitous in childhood and occur across all ages, this is the first publication to focus on this topic in detail. In its first section, the basic, translational, and clinical background of parasomnias is reviewed. In the second section of the book, the clinical aspects of the disorders of arousal that commonly occur in children, including confusional arousals, sleepwalking and sleep terrors, are discussed. The third section deals with the parasomnias usually associated with REM sleep. The fourth section deals with a group of parasomnias under the group heading of "other parasomnias". The fifth section deals with sleep-related movement disorders and other variants that are often included in the differential diagnosis of the parasomnias. The sixth section discusses the pharmacologic, behavioral and psychiatric management of the parasomnias.

2010 - The Parasomnias and other sleep-related movement disorders [Prefazione o Postfazione]
M. J., Thorpy; Plazzi, Giuseppe

Parasomnias and other sleep-related movement disorders provides scientific and clinical information on abnormal movement disorders during sleep for all health care workers interested in disorders of sleep.

2009 - Actigraphy in the assessment of insomnia: a quantitative approach [Articolo su rivista]
Natale, V.; Plazzi, G.; Martoni, M.

2009 - Agrypnia Excitata: a microneurographic study of muscle sympathetic nerve activity [Articolo su rivista]
Donadio, VINCENZO ANGELO; Montagna, Pasquale; Pennisi, M.; Rinaldi, R.; Di Stasi, V.; Avoni, Patrizia; Bugiardini, E.; Giannoccaro, M. P.; Cortelli, Pietro; Plazzi, Giuseppe; Baruzzi, Agostino; Liguori, Rocco

2009 - Association of restless legs syndrome with nocturnal eating: a case-control study [Articolo su rivista]
Provini, F.; Antelmi, E.; Vignatelli, L.; Zaniboni, A.; Naldi, G.; Calandra-Buonaura, G.; Vetrugno, R.; Plazzi, G.; Montagna, P.

2009 - Body mass index-independent metabolic alterations in narcolepsy with cataplexy [Articolo su rivista]
Poli, F.; Plazzi, G.; Di Dalmazi, G.; Ribichini, D.; Vicennati, V.; Pizza, F.; Mignot, E.; Montagna, P.; Pasquali, R.; Pagotto, U.

2009 - Cataplexy: An affair of pleasure or an unpleasant affair? [Articolo su rivista]
Tucci, V.; Plazzi, G.

2009 - Detection of sleep onset by analysis of slow eye movements: A preliminary study of MSLT recordings [Articolo su rivista]
Fabbri, M.; Provini, F.; Magosso, E.; Zaniboni, A.; Bisulli, A.; Plazzi, G.; Ursino, M.; Montagna, P.

2009 - Distribution of neurochemical abnormalities in patients with narcolepsy with cataplexy: an in vivo brain proton MR spectroscopy study [Articolo su rivista]
Tonon, Caterina; Franceschini, Christian; Testa, Claudia; Manners, DAVID NEIL; Poli, Francesca; Mostacci, B.; Mignot, E.; Montagna, Pasquale; Barbiroli, Bruno; Lodi, Raffaele; Plazzi, Giuseppe

2009 - Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset [Articolo su rivista]
Aran, A.; Lin, L.; Nevsimalova, S.; Plazzi, G.; Hong, S. C.; Weiner, K.; Zeitzer, J.; Mignot, E.

2009 - Erratum: Narcolepsy is strongly associated with the T-cell receptor alpha locus (Nature Genetics (2009) 41 (708-711)) [Articolo su rivista]
Hallmayer, J.; Faraco, J.; Lin, L.; Hesselson, S.; Winkelmann, J.; Kawashima, M.; Mayer, G.; Plazzi, G.; Nevsimalova, S.; Bourgin, P.; Hong, S. S. -C.; Honda, Y.; Honda, M.; Hogl, B.; Longstreth, W. T.; Montplaisir, J.; Kemlink, D.; Einen, M.; Chen, J.; Musone, S. L.; Akana, M.; Miyagawa, T.; Duan, J.; Desautels, A.; Erhardt, C.; Hesla, P. E.; Poli, F.; Frauscher, B.; Jeong, J. -H.; Lee, S. -P.; Ton, T. G. N.; Kvale, M.; Kolesar, L.; Dobrovolna, M.; Nepom, G. T.; Salomon, D.; Wichmann, H. -E.; Rouleau, G. A.; Gieger, C.; Levinson, D. F.; Gejman, P. V.; Meitinger, T.; Young, T.; Peppard, P.; Tokunaga, K.; Kwok, P. -Y.; Risch, N.; Mignot, E.

2009 - L'analisi dell'accordo fra osservatori e delle fonti di variabilità come strumento per il miglioramento della qualità in medicina legale [Abstract in Atti di Convegno]
Ingravallo, F; Vignatelli, L; Plazzi, G; Cicognani, A

2009 - Las Parasomnias [Capitolo/Saggio]
Plazzi, G.; Lugaresi, E.

In questo capitolo vengono descritti, tra l'altro, le parasonnie quali le allucinazioni ipnagogiche, la jactatio capitis nocturna, il bruxismo, il mioclono propriospinale, il terrore notturno, il sonnambulismo, le parasonnie legate ad epilessia notturna del lobo frontale, le alterazioni del comportamento durante il sonno REM ed il mioclono facio-mandibolare.

2009 - Narcolepsy is strongly associated with the T-cell receptor alpha locus [Articolo su rivista]
Hallmayer, J.; Faraco, J.; Lin, L.; Hesselson, S.; Winkelmann, J.; Kawashima, M.; Mayer, G.; Plazzi, G.; Nevsimalova, S.; Bourgin, P.; Hong, S. S.; Honda, Y.; Honda, M.; Hogl, B.; Longstreth, W. T. Jr.; Montplaisir, J.; Kemlink, D.; Einen, M.; Chen, J.; Musone, S. L.; Akana, M.; Miyagawa, T.; Duan, J.; Desautels, A.; Erhardt, C.; Hesla, P. E.; Poli, F.; Frauscher, B.; Jeong, J. H.; Lee, S. P.; Ton, T. G.; Kvale, M.; Kolesar, L.; Dobrovolnà, M.; Nepom, G. T.; Salomon, D.; Wichmann, H. E.; Rouleau, G. A.; Gieger, C.; Levinson, D. F.; Gejman, P. V.; Meitinger, T.; Young, T.; Peppard, P.; Tokunaga, K.; Kwok, P. Y.; Risch, N.; Mignot, E.

2009 - Narcolepsy-like syndrome in multiple sclerosis [Articolo su rivista]
Vetrugno, R.; Stecchi, S.; Plazzi, G.; Lodi, R.; D’Angelo, R.; Alessandria, M.; Cortelli, P.; Montagna, P.

2009 - Psychogenic nocturnal stridor in a child: a case report [Articolo su rivista]
Vetrugno, Roberto; Franceschini, Christian; D'Angelo, R.; Antelmi, Elena; Moghadam, K. K.; Montagna, Pasquale; Vicini, C.; Plazzi, Giuseppe

2009 - Sleep and time course of consolidation of visual discrimination skills in patients with narcolepsy-cataplexy [Articolo su rivista]
Cipolli, C.; Campana, G.; Campi, C.; Mattarozzi, K.; Mazzetti, M.; Tuozzi, G.; Vandi, S.; Vignatelli, L.; Plazzi, G.

2009 - Sleep polygraphic study of children and adolescents with narcolepsy/cataplexy [Articolo su rivista]
Ferri, R.; Franceschini, Christian; Zucconi, M.; Drago, V.; Manconi, M.; Vandi, Stefano; Poli, Francesca; Bruni, O.; Plazzi, Giuseppe

2009 - Status dissociatus evolving from REM sleep behaviour disorder in multiple system atrophy [Articolo su rivista]
Vetrugno, R.; Alessandria, M.; D'Angelo, R.; Plazzi, G.; Provini, F.; Cortelli, P.; Montagna, P.

2008 - A quantitative statistical analysis of the submentalis muscle EMG amplitude during sleep in normal controls and patients with REM sleep behavior disorder [Articolo su rivista]
Ferri, R.; Manconi, M.; Plazzi, G.; Bruni, O.; Vandi, S.; Montagna, P.; Ferini-Strambi, L.; Zucconi, M.

2008 - Cataplexy features in childhood narcolepsy [Articolo su rivista]
Serra, L.; Montagna, P.; Mignot, E.; Lugaresi, E.; Plazzi, G.

2008 - Clinical, behavioural and polysomnographic correlates of cataplexy in patients with narcolepsy/cataplexy [Articolo su rivista]
Mattarozzi, Katia; Bellucci, Claudia; Campi, Claudio; Cipolli, Carlo; Ferri, R.; Franceschini, Christian; Mazzetti, Michela; Russo, Paolo Maria; Vandi, Stefano; Vignatelli, L.; Plazzi, Giuseppe

2008 - Daytime sleepiness and neural cardiac modulation in sleep-related breathing disorders [Articolo su rivista]
Lombardi, C.; Parati, G.; Cortelli, P.; Provini, F.; Vetrugno, R.; Plazzi, G.; Vignatelli, L.; Di Rienzo, M.; Lugaresi, E.; Mancia, G.; Montagna, P.; Castiglioni, P.

2008 - Group I nonreciprocal inhibition in primary restless legs sindrome [Articolo su rivista]
Scaglione, C.; Vetrugno, R.; Plazzi, G.; Rizzo, G.; Provini, F.; Montagna, P.; Martinelli, P.

Abstract: Electrophysiological investigations of restless legs syndrome (RLS) have found spinal circuits impinging on motoneurones. We evaluated the H reflex threshold, latency, the Hmax/Mmax ratio, and the short latency autogenic inhibition in 7 patients with RLS and 10 age-matched controls by testing the excitability changes in soleus H reflex Ib interneuron function. A significant reduction in Ib inhibition at 4 (P 0.043), 5 (P 0.007), and 6 ms (P 0.001) of H reflex conditioning interstimulus interval was found in RLS patients. Data support the hypothesis that altered group I nonreciprocal inhibition is implicated in enhancing the spinal circuitry excitability of RLS, and are consistent with the view of an abnormal supraspinal drive to spinal interneurons in RLS. © 2007 Movement Disorder Society

2008 - Identifying insomnia using actigraphy: quantitative criteria [Relazione in Atti di Convegno]
Martoni, M.; Plazzi, G.; Natale, V.

2008 - Interrater reliability as quantitative end-point for legal medicine in work ability assessment: a lesson from an epidemiological study applied to a neurological disease [Abstract in Atti di Convegno]
Ingravallo, F.; Plazzi, G.; Vignatelli, L.

Plazzi, Giuseppe; Poli, Francesca; Franceschini, Christian; Parmeggiani, Antonia; Pirazzoli, Piero; Bernardi, Filippo; E., Mignot; Cicognani, Alessandro; Montagna, Pasquale

We report on the outcome of intravenous high-dose immunoglobulin (IVIg) treatment in four children with narcolepsy and cataplexy, in whom the early diagnosis and the extreme disease severity were indications for this potentially efficacious therapy. One of four patients showed an objective and persistent improvement in clinical features during and after IVIg treatment. Our data partially support the recent report of the efficacy of IVIg treatment in early diagnosed narcolepsy with cataplexy and support the need for a controlled multicenter clinical trial on IVIg in narcolepsy.

2008 - Medico-legal assessment of disability in narcolepsy: an interobserver reliability study [Articolo su rivista]
Ingravallo, Francesca; Vignatelli, Luca; Brini, Martina; Brugaletta, Concetta; Franceschini, Christian; Lugaresi, Federica; M. C., Manca; S., Garbarino; Montagna, Pasquale; Cicognani, Alberto; Plazzi, Giuseppe

2008 - Nocturnal aspects of narcolepsy with cataplexy [Articolo su rivista]
Plazzi, G.; Serra, L.; Ferri, R.

2008 - Normative europee su eccessiva sonnolenza diurna e sicurezza stradale [Relazione in Atti di Convegno]
Ingravallo, F.; Plazzi, G.

La disciplina della Comunità Europea sull’idoneità alla guida è contenuta nell’Allegato III alla Direttiva del Consiglio 91/439/CEE del 29 luglio 1991 sulle patenti di guida, che dispone a quali accertamenti e limitazioni i guidatori debbano essere sottoposti in caso siano affetti da malattie o condizioni invalidanti che compromettono l’idoneità alla guida. Fra queste non risultano annoverate la Sindrome delle apnee ostruttive del sonno (OSAS), la Narcolessia o altre malattie associate ad eccessiva sonnolenza diurna (ESD). Molti Paesi della Comunità Europea, ma non l’Italia, hanno implementato la Direttiva 91/439/CEE con disposizioni nazionali che prevedono restrizioni al rilascio della patente di guida in caso di OSAS e/o Narcolessia. Il capitolo analizza tali disposizioni, prospettando anche alcune strategie per ovviare alla mancanza di una normativa italiana in materia.

2008 - Praxis-induced seizures misdiagnosed as cataplexy: a case report [Articolo su rivista]
Plazzi, Giuseppe; Tinuper, Paolo

2008 - Searching for a marker of REM sleep behavior disorder: submentalis muscle EMG amplitude analysis during sleep in patients with narcolepsy/cataplexy [Articolo su rivista]
Ferri, R.; Franceschini, Christian; Zucconi, M.; Vandi, Stefano; Poli, Francesca; Bruni, O.; Cipolli, Carlo; Montagna, Pasquale; Plazzi, Giuseppe

2008 - Sleep-related violence: aspetti clinici e medico-legali [Articolo su rivista]
Ingravallo, F.; Plazzi, G.; Cicognani, A.

2008 - Story-like organization of REM-dreams in patients with narcolepsy-cataplexy [Articolo su rivista]
Cipolli, C; Bellucci, L; Mattarozzi, K; Mazzetti, M; Tuozzi, G; Plazzi, G.

Narcolepsy with cataplexy (NC) is a neurological disorder characterized by excessive daytime sleepiness and an altered architecture of sleep. Previous laboratory studies have shown that frightening, bizarre and visually vivid contents are more frequent in dream experiences developed during the first period of REM sleep by NC patients than healthy subjects. As the structural organization of dream experiences of NC patients has not been yet examined, we compared its indicators in dream reports collected from a sample of NC patients and their matched controls. During an experimental night two awakenings were provoked after 8min of REM sleep in the first and third sleep cycle. Dream reports were analyzed using the rules of story grammars, capable of identifying units larger than single contents and describing their story-like organization. While dream recall (about 85%) was comparable in NC patients and controls, 1st-REM dream reports were longer in NC patients. Statistical analyses on the 12 NC patients and their matched controls who reported dreams after both REM periods showed that dream experiences occurring in 1st-REM reports of NC patients were longer and had a more complex organization than those of controls. These findings suggest that the cognitive processes underlying dream generation reach their optimal functioning earlier in the night in NC patients than in normal subjects.

2008 - Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13 [Articolo su rivista]
Kemlink, D.; Plazzi, G.; Vetrugno, R.; Provini, F.; Polo, O.; Stiasny-Kolster, K.; Oertel, W.; Nevsimalova, S.; Sonka, K.; Hogl, B.; Frauscher, B.; Hadjigeorgiou, G. M.; Pramstaller, P. P.; Lichtner, P.; Meitinger, T.; Muller-Myshok, B.; Winkelmann, J.; Montagna, P.

2008 - Sympathetic and cardiovascular activity during cataplexy in narcolepsy [Articolo su rivista]
Donadio, V.; Plazzi, Giuseppe; Vandi, Stefano; Franceschini, Christian; Karlsson, T.; Montagna, Pasquale; Vetrugno, Roberto; Bugiardini, E.; Mignot, E.; Liguori, Rocco

2007 - Augmentation of restless legs syndrome with long-term tramadol treatment [Articolo su rivista]
Vetrugno, R.; La Morgia, C.; D'Angelo, R.; Loi, D.; Provini, F.; Plazzi, G.; Montagna, P.

2007 - Catathrenia (nocturnal groaning): an abnormal respiratory pattern during sleep [Articolo su rivista]
Vetrugno, R.; Lugaresi, E.; Plazzi, G.; Provini, F.; D'Angelo, R.; Montagna, P.

2007 - Impaired cortical and autonomic arousal during sleep in multiple system atrophy [Articolo su rivista]
Vetrugno, R.; D'Angelo, R.; Cortelli, P.; Plazzi, G.; Vignatelli, L.; Montagna, P.

2007 - La Sindrome delle Apnee Ostruttive in Sonno: una importante causa di incidenti stradali [Capitolo/Saggio]
S., Garbarino; E., Bonanni; Ingravallo, Francesca; S., Mondini; A., Sanna; Plazzi, Giuseppe

Solo negli ultimi anni ha iniziato a diffondersi una corretta percezione dei rischi (di incidenti o near/miss accidents alla guida, domestici, sul lavoro) e dei costi sociali e sanitari legati all’eccessiva sonnolenza diurna, quale principale sintomo di alcune malattie, ovvero risultante di cambiamenti in atto nella nostra società, che impongono modificazioni del sonno sia di tipo meramente quantitativo (privazione cronica di sonno) che quali-quantitativo (organizzazione del lavoro a turni). Il capitolo affronta gli aspetti clinici (fisiopatologia, diagnosi, trattamento) e medico-legali della Sindrome delle Apnee ostruttive del sonno (OSAS), che rappresenta la più frequente causa di sonnolenza patologica. Dalla lettera di George et al. pubblicata su Lancet nel 1987, nella quale gli autori denunciavano un rischio di incidenti negli OSAS più che doppio rispetto ai controlli, molti studi hanno evidenziato il maggior rischio di incidenti alla guida di questi pazienti, con costi diretti ed indiretti che nel nostro Paese sono stati stimati ammontare, secondo dati dell’Istituto Superiore di Sanità (2006) a 838.014.000 euro. Parallelamente, molti studi hanno dimostrato l’efficacia della CPAP nel ridurre il rischio di incidenti alla guida, tanto che è stato calcolato che se negli USA tutti i pazienti affetti da OSAS venissero trattati con CPAP si salverebbero 980 vite/anno e si risparmierebbero 11,1 miliardi di dollari/anno (ogni $ speso per CPAP farebbe risparmiare 3,49 $ di costi incidenti). Vengono quindi discusse le strategie di prevenzione degli incidenti e la situazione legislativa dei Paesi europei su OSAS e idoneità alla guida.

2007 - Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep [Articolo su rivista]
Tinuper, P.; Provini, F.; Bisulli, F.; Vignatelli, L.; Plazzi, G.; Vetrugno, R.; Montagna, P.; Lugaresi, E.

2007 - Pontine hyperperfusion in sporadic hyperekplexia [Articolo su rivista]
Vetrugno, R.; Mascalchi, M.; Vella, A.; Della Nave, R.; Guerrini, L.; Vattimo, A.; del Giudice, E. M.; Plazzi, G.; D'Angelo, R.; Greco, G.; Montagna, P.

2007 - Proton Magnetic Resonance Spectroscopy Study of Brain Metabolism in Obstructive Sleep Apnoea Syndrome before and after Continuous Positive Airway Pressure Treatment [Articolo su rivista]
Tonon, C.; Vetrugno, R.; Lodi, R.; Gallassi, R.; Provini, F.; Iotti, S.; Plazzi, G.; Montagna, P.; Lugaresi, E.; Barbiroli, B.

Study Objectives: Obstructive sleep apnoea syndrome (OSAS) causes sleep related oxygen desaturation, excessive daytime sleepiness (EDS), and cognitive impairment. The role of hypoxic brain damage, sleep fragmentation, and the associated comorbidities (hypertension, vascular disorders) in the pathogenesis of cognitive deficits remains controversial. The aim of this study was to evaluate the cerebral metabolism of OSAS patients in vivo before and after CPAP treatment. Design and Patients: Fourteen OSAS patients without cardiovascular or cerebrovascular impairment underwent the same protocol before and after 6 months of CPAP including: overnight videopolysomnography (VPSG), Multiple Sleep Latency Test (MSLT), and within the next 2 days neuropsychological and 1H-MRS evaluations. Single voxel 1H-MRS was performed in the parietal-occipital cortex, and absolute concentrations of N-acetyl-aspartate (NAA), creatine, and choline were measured, acquiring spectra at multiple echo-times and using water as internal standard. Ten matched controls were also studied. Results: OSAS patients had a mean RDI of 58/hr, a mean arousal index of 57/hr, and a mean nadir SpO2 of 71%. Before CPAP, all patients showed a normal global cognitive functioning, with only a small number of pathological tasks in working memory and attention tests in a minority of patients. CPAP therapy was effective in resolving sleep apnoea and normalizing sleep structure, and improving EDS and neuropsychological alterations. Before CPAP treatment cortical [NAA] in OSAS (11.86 mM±0.80, mean±SD) was significantly lower than in controls (12.85±0.93; P = 0.01) and positively correlated with minimum SpO2 during sleep (r = 0.69; P = 0.006) and MSLT scores (r = 0.62; P = 0.01). Cortical [NAA] reduction persisted after therapy (11.94±1.33; P = 0.87 versus pre-CPAP). Conclusions: OSAS patients have cortical metabolic changes consistent with neuronal loss even in the absence of vascular comorbidities. Metabolic changes persisted after CPAP in the absence of EDS, nocturnal arousals, and major cognitive deficits, likely related to hypoxic damage prior to CPAP treatment.

2007 - Sleep-related stridor due to dystonic vocal cord motion and neurogenic tachypnea/tachycardia in multiple system atrophy [Articolo su rivista]
Vetrugno, R.; Liguori, R.; Cortelli, P.; Plazzi, G.; Vicini, C.; Campanini, A.; D'Angelo, R.; Provini, F.; Montagna, P.

2007 - Sleep-wake and body core temperature rhythms in multiple sclerosis with fatigue [Articolo su rivista]
Vetrugno, R.; Stecchi, S.; Scandellari, C.; Pierangeli, G.; Sabattini, L.; D'Angelo, R.; Provini, F.; Plazzi, G.; Cortelli, P.; Montagna, P.

2007 - Studio RM multimodale nella narcolessia: correlati neurometabolici, morfometrici e di attivazione funzionale cerebrale- Studio RM multimodale nella narcolessia: correlati neurometabolici, morfometrici e di attivazione funzionale cerebrale (UO Prof Lodi) [Working paper]
Plazzi, G.; Lodi, R.

L'obiettivo del progetto della Unità di Ricerca del Dipartimento di Medicina Clinica e Biotecnologia Applicata, Università di Bologna, è identificare e correlare tra loro in pazienti narcolettici anomalie neurometaboliche, strutturali, e di attivazione cerebrale. I diversi aspetti metabolici, morfologici e d'attivazione funzionale cerebrale saranno indagati utilizzando tecniche di risonanaza magnetica avanzate e quantitative quali: -spettroscopia RM del protone (1H-MRS) -voxel based morphometry MRI (VBM-MRI) -MRI funzionale(f-MRI) I risultati degli studi di risonanza magnetica verranno messi in relazione con i risultati clinici e polisonnografici (Unità di Ricerca diretta dal Dr. Plazzi), neuropsicologici (Unità di Ricerca diretta dal Prof. Tuozzi), di analisi spettrale (Unità di Ricerca diretta dal Prof Ferrillo) e genetici (Unità di Ricerca diretta dal Prof Gambardella) ottenuti negli stessi pazienti. Come descritto nel "Modello A" lo sforzo complessivo darà un contributo alla identificazione dei multipli determinanti della complessa espressione fenotipica della narcolessia umana.

2007 - Time structure analysis of leg movements during sleep in REM sleep behavior disorder [Articolo su rivista]
Manconi, M.; Ferri, R.; Zucconi, M.; Fantini, M. L.; Plazzi, G.; Ferini-Strambi, L.

2007 - Treatment of narcolepsy with cataplexy [Articolo su rivista]
Plazzi, G.; Montagna, P.; Provini, F.; Albani, F.; Riva, R.

2006 - Autogenic inhibition (Ib inhibition) in primary restless legs syndrome [Relazione in Atti di Convegno]
Martinelli, P.; Scaglione, C.; Vetrugno, R.; Plazzi, G.; Provini, F.; Montagna, P.

2006 - Caratteristiche strutturali della attività mentali elaborate durante il sonno REM nei pazienti narcolettici [Relazione in Atti di Convegno]
Mattarozzi, K.; Mazzetti, M.; Campi, C.; Bellucci, C.; Franceschini, C.; Plazzi, G.; Tuozzi, G.; Cipolli, C.

2006 - Different periodicity and time structure of leg movements during sleep in narcolepsy/cataplexy and restless legs syndrome [Articolo su rivista]
Ferri, R.; Zucconi, M.; Manconi, M.; Bruni, O.; Ferini-Strambi, L.; Vandi, S.; Montagna, P.; Mignot, E.; Plazzi, G.

2006 - Excessive daytime sleepiness and subjective sleep quality in patients with nocturnal frontal lobe epilepsy: a case-control study [Articolo su rivista]
Vignatelli, L.; Bisulli, F.; Naldi, I.; Ferioli, S.; Pittau, F.; Provini, F.; Plazzi, G.; Vetrugno, R.; Montagna, P.; Tinuper, P.

2006 - IB autogenic inhibition in primary restless legs syndrome [Relazione in Atti di Convegno]
Scaglione, C.; Vetrugno, R.; Plazzi, G.; Provini, F.; Montagna, P.; Martinelli, P.

2006 - Interobserver reliability in the assessment of disablement in patients with narcolepsy [Abstract in Atti di Convegno]
Ingravallo, Francesca; Vignatelli, Luca; Brini, M.; Franceschini, Christian; Lugaresi, F.; Brugaletta, C.; Manca, M. C.; Montagna, Pasquale; Cicognani, Alberto; Plazzi, Giuseppe

2006 - Mitochondrial neurogastrointestinal encephalomyopathy: Evidence of mitochondrial DNA depletion in the small intestine [Articolo su rivista]
Giordano, C.; Sebastiani, M.; Plazzi, G.; Travaglini, C.; Sale, P.; Pinti, Marcello; Tancredi, A.; Liguori, R.; Montagna, P.; Bellan, M.; Valentino, M. L.; Cossarizza, Andrea; Hirano, M.; D'Amati, G.; Carelli, V.

Background & Aims: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease clinically defined by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy, white-matter changes in brain magnetic resonance imaging, and mitochondrial abnormalities. Loss-of-function mutations in thymidine phosphorylase gene induce pathologic accumulations of thymidine and deoxyuridine that in turn cause mitochondrial DNA (mtDNA) defects (depletion, multiple deletions, and point mutations). Our study is aimed to define the molecular basis of gastrointestinal dysmotility in a case of MNGIE. Methods: By using laser capture microdissection techniques, we correlated histologic features with mtDNA abnormalities in different tissue components of the gastrointestinal wall in a MNGIE patient and ten controls. Results: The patient's small intestine showed marked atrophy and mitochondrial proliferation of the external layer of muscularis propria. Genetic analysis revealed selective depletion of mtDNA in the small intestine compared with esophagus, stomach, and colon, and microdissection analysis revealed that mtDNA depletion was confined to the external layer of muscularis propria. Multiple deletions were detected in the upper esophagus and skeletal muscle. Site-specific somatic point mutations were detected only at low abundance both in the muscle and nervous tissue of the gastrointestinal tract. Analysis of the gastrointestinal tract from 10 controls revealed a non-homogeneous distribution of mtDNA content; the small intestine had the lowest levels of mtDNA. Conclusion: Atrophy, mitochondrial proliferation, and mtDNA depletion in the external layer of muscularis propria of small intestine indicate that visceral myopathy is responsible for gastrointestinal dysmotility in this MNGIE patient.

2006 - Narcolepsy-cataplexy associated with precocious puberty: a new form of hypothalamic dysfunction [Abstract in Atti di Convegno]
Plazzi, Giuseppe; Parmeggiani, Antonia; Mignot, E.; Lin, L.; Franceschini, Christian; Scano, MARIA CARMEN; Posar, Annio; Bernardi, Filippo; Lodi, Raffaele; Tonon, Caterina; Barbiroli, Bruno; Cicognani, Alessandro; Montagna, Pasquale

2006 - Narcolepsy-cataplexy associated with precocious puberty: a novel hypothalamic dysfunction [Articolo su rivista]
Plazzi, G.; Parmeggiani, A.; Mignon, E.; Lin, L.; Scano, Mc.; Posar, A.; Bernardi, F.; Lodi, R.; Tonon, C.; Barbiroli, B.; Montagna, P.; Cicognani, A.

In children, narcolepsy may be the symptom of a brain lesion or genetic disease. The authors report two cases with severe narcolepsy-cataplexy emerging in childhood in close temporal association with obesity and precocious puberty.

2006 - Narcolessia-cataplessia due casi particolari [Abstract in Atti di Convegno]
M., Fabi; S., Colonna; L., Bertelli; I., Corsini; Tassinari, Davide; Parmeggiani, Antonia; Plazzi, Giuseppe

2006 - New approaches to the study of periodic leg movements during sleep in restless legs syndrome [Articolo su rivista]
Ferri, R.; Zucconi, M.; Manconi, M.; Plazzi, G.; Bruni, O.; Ferini-Strambi, L.

2006 - Nocturnal baroreflex sensitivity and heart rate variability are markers of excessive daytime sleepiness in sleep related breathing disorders [Relazione in Atti di Convegno]
Lombardi, C.; Castiglioni, P.; Cortelli, P.; Provini, F.; Vetrugno, R.; Plazzi, G.; Vignatelli, L.; DI RIENZO, M.; Lugaresi, E.; Mancia, G.; Montagna, P.; Parati, G. P.

2006 - Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study [Articolo su rivista]
Vetrugno, R.; Manconi, M.; Ferini-Strambi, L.; Provini, F.; Plazzi, G.; Montagna, P.

2006 - Nocturnal frontal lobe epilepsy and arousal disorders: chance association or common mechanisms? [Abstract in Atti di Convegno]
Montagna, Pasquale; Bisulli, Francesca; Naldi, Ilaria; Vignatelli, Luca; Provini, Federica; Plazzi, Giuseppe; Vetrugno, Roberto; Tinuper, Paolo

2006 - Polisomnographic and pharmacokinetic findings in levodopa-induced augmentation of restless legs syndrome [Articolo su rivista]
Vetrugno, R.; Contin, M.; Baruzzi, A.; Provini, F.; Plazzi, G.; Montagna, P.

2006 - Reliability of narcolepsy assessment for disability benefit [Abstract in Atti di Convegno]
Ingravallo, Francesca; Vignatelli, Luca; Brini, M; Franceschini, Christian; Manca, M; Montagna, Pasquale; Cicognani, Alberto; Plazzi, Giuseppe

2006 - Seeking a central autonomic hallmark in early hypertensive patients: a study of circadian rhythms and state-dependent variations of blood pressure (BP), heart rate (HR), body core temperature (BCT) [Abstract in Atti di Convegno]
Pierangeli, Giulia; Montagna, Pasquale; Barletta, Giorgio; Provini, Federica; Plazzi, Giuseppe; Vetrugno, Roberto; Guaraldi, P.; Zaniboni, Anna; Vandi, Stefano; Zanigni, Stefano; Ribani, M. A.; Marchetta, F.; Portaluppi, F.; Cortelli, Pietro

2006 - Semantic priming effect during REM-sleep inertia in patients with narcolepsy [Articolo su rivista]
Mazzetti, M.; Campi, C.; Mattarozzi, K.; Plazzi, G.; Tuozzi, G.; Vandi, S.; Vignatelli, L.; Cipolli, C.

2006 - Sonno e apprendimento di abilità motorie nei pazienti narcolettici [Relazione in Atti di Convegno]
Campi, C.; Mattarozzi, K.; Mazzetti, M.; Bolletta, L.; Vandi, S.; Plazzi, G.; Cipolli, C.

2006 - The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG) [Articolo su rivista]
Zucconi, M.; Ferri, R.; Allen, R.; Baier, P. C.; Bruni, O.; Chokroverty, S.; Ferini-Strambi, L.; Fulda, S.; Garcia-Borreguero, D.; Hening, W. A.; Hirshkowitz, M.; Hogl, B.; Hornyak, M.; King, M.; Montagna, P.; Parrino, L.; Plazzi, G.; Terzano, M. G.

2006 - The time structure of the cyclic alternating pattern during sleep [Articolo su rivista]
Ferri, R.; Bruni, O.; Miano, S.; Plazzi, G.; Spruyt, K.; Gozal, D.; Terzano, M. G.

2006 - Trombocitemia transitoria del neonato [Relazione in Atti di Convegno]
Pagano, R; Roversi, Mf; Plazzi, G; Cellini, M; Quitadamo, L; Bonaccorsi, G; Artusi, T; Ori, L; Paolucci, P; Ferrari, Fabrizio

No abstract

2005 - A pilot double-blind placebo-controlled trial of low-dose pramipexole in sleep-related eating disorder [Articolo su rivista]
Provini, F.; Albani, F.; Vetrugno, R.; Vignatelli, L.; Lombardi, C.; Plazzi, G.; Montagna, P.

2005 - All-night EEG power spectral analysis of the cyclic alternating pattern components in young adult subjects [Articolo su rivista]
Ferri, R.; Bruni, O.; Miano, S.; Plazzi, G.; Terzano, M. G.

2005 - An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome [Articolo su rivista]
Wunderlich, G. R.; Evans, K. R.; Sills, T.; Pollentier, S.; Reess, J.; Allen, R. P.; Hening, W.; Walters, A. S.; Adler, C.; Aksu, M.; Allen, R. P.; Anderson, M.; Israel, S. A.; Jimenez, W. B.; Bassetti, C.; Bliwise, D. L.; Broch, L. L.; Buchholz, D.; Chokroverty, S.; Clavadetscher, S.; Coccagna, G.; de Mello, M. T.; de Weerd, A. W.; Dhar, A.; Ehrenberg, B.; Eisensehr, I.; Ekbom, Jr. K.; Garcia-Borreguero, D.; Gurecki, P.; Hallett, M.; Hening, W. A.; Hirsch, L.; Hogl, B.; Horiguchi, J.; Hornyak, M.; Kryger, M.; Larrosa, O.; Lebrocq, C.; Lipinski, J. F.; Ljungdahl, A.; Lugaresi, E.; Masood, A.; Miele, F.; Montagna, P.; Mosko, S.; Newman, S.; Oertel, W. H.; O'Keeffe, S.; Oldani, A.; Ondo, W. G.; Phillips, B.; Picchietti, D.; Plazzi, G.; Poceta, J. S.; Provini, F.; Reiners, C.; Rich, G. B.; Rijsman, R. M.; Rosen, R.; Rye, D. B.; Scrima, L.; Shafor, R.; Sharon, D.; Silber, M.; Skowrow, R.; Smith, R.; Stiasny, K.; Trenkwalder, C.; Tufik, S.; Vanek, Z.; Voderholzer, U.; Wagner, M.; Wetter, T. C.; Winkelmann, J.; Zak, R.; Zucconi, M.

Background and purpose: Restless legs syndrome (RLS) is a common central nervous system disorder; however, there is currently a lack of well-validated and easily-administered measures of RLS severity available. The International Restless Legs Syndrome Study Group has recently developed a 10-item scale to meet this need. The International Restless Legs Severity Scale (IRLS) has been shown to have a high degree of reliability, validity, and internal consistency. In order to further demonstrate the validity of the IRLS, the present study examined the relationship between scores on individual IRLS items and overall RLS severity. Patients and methods: The 10-item IRLS was administered to 19 6 RLS patients. Option characteristic curves (the probability of scoring different options for a given item as a function of overall IRLS score) were generated in order to illustrate the scoring patterns for each item across the range of total RLS severity. Item characteristic curves (the expected score on an item as a function of overall IRLS score) were also generated to illustrate the relationship between scores on the individual items and total RLS severity. Results: The IRLS items demons trated excellent item response properties, with option and item characteristic curves closely approximating those of an ideal item. Item 3 (relief of arm or leg discomfort from moving around) was the most problematic item in that a 'floor' effect was evident; however, the item response characteristics for this item were still acceptable. Conclusions: Each IRLS item showed a good relationship between responses on that item and overall RLS severity, providing further evidence for the validity of the IRLS as a measure of RLS severity in RLS patients. © 2004 Elsevier B.V. All rights reserved.

2005 - Cardiovascular reflexes in patients with recent onset hypertension [Abstract in Atti di Convegno]
Pierangeli, G.; Cortelli, P.; Barletta, G.; Provini, F.; Plazzi, G.; Vetrugno, R.; Vandi, S.; Zaniboni, A.; Ribani, M. A.; Marchetta, F.; Portaluppi, F.; Montagna, P.

2005 - Computer-Assisted Detection of Nocturnal Leg Motor Activity in Patients with Restless Legs Syndrome and Periodic Leg Movements During Sleep [Articolo su rivista]
Ferri, R.; Zucconi, M.; Manconi, M.; Bruni, O.; Miano, S.; Plazzi, G.; Ferini-Strambi, L.

2005 - Continuous motor unit activity syndromes: A video-polysomnographic study [Articolo su rivista]
Vetrugno, R.; Liguori, R.; Provini, F.; Plazzi, G.; Montagna, P.

2005 - Depletion of mtDNA limited to the external layer of muscularis propria induces gastrointestinal dysmotility in a MNGIE patient [Abstract in Atti di Convegno]
Bellan, M.; Giordano, C.; Sebastiani, M.; Plazzi, Giuseppe; Travaglini, C.; Pinti, M.; Sale, P.; Zani, M.; Liguori, Rocco; Montagna, Pasquale; Baruzzi, Agostino; Valentino, M. L.; Cossarizza, A.; Hirano, M.; D'Amati, G.; Carelli, Valerio

2005 - Driving licence regulations for narcolepsy in European Community [Relazione in Atti di Convegno]
Ingravallo, F.; Vignatelli, L.; Lugaresi, F.; Montagna, P.; Cicognani, A.; Plazzi, G.

2005 - Eccessiva sonnolenza diurna: aspetti clinici, medico-legali e diagnosi differenziale [Relazione in Atti di Convegno]
Plazzi, G.; Ingravallo, F.; Vignatelli, L.

2005 - Evaluation of the circadian rhythm of body core temperature (BCT) in recent onset essential hypertension [Abstract in Atti di Convegno]
Pierangeli, G.; Montagna, P.; Barletta, G.; Provini, F.; Plazzi, G.; Vetrugno, R.; Zaniboni, A.; Vandi, S.; Ribani, M. A.; Marchetta, F.; Portaluppi, F.; Cortelli, P.

2005 - Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives [Articolo su rivista]
Ohayon, M. M.; Ferini-Strambi, L.; Plazzi, G.; Smirne, S.; Castronovo, V.

2005 - Frequency of Parasomnias in patients with Nocturnal Frontal Lobe Epilepsy (NFLE) and their relatives [Relazione in Atti di Convegno]
Bisulli, F.; Naldi, I.; Vignatelli, L.; Ferrioli, S.; Provini, F.; Plazzi, G.; Vetrugno, R.; Montagna, P.; Tinuper, P.

2005 - Health-related quality of life in patients with narcolespsy: a prospective cohort study [Relazione in Atti di Convegno]
Plazzi, G.; Vignatelli, L.; Peschechera, F.; Ingravallo, F.; Montagna, P.; D'Alessandro, R.

2005 - How age influences the expression of narcolepsy [Articolo su rivista]
Ohayon, M. M.; Ferini-Strambi, L.; Plazzi, G.; Smirne, S.; Castronovo, V.

2005 - Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias [Articolo su rivista]
Vignatelli, L.; Bisulli, F.; Zaniboni, A.; Naldi, I.; Fares, Je.; Provini, F.; Vetrugno, R.; Plazzi, G.; Tinuper, P.; Montagna, P.

2005 - Memoria procedurale e dichiarativa durante il sonno di pazienti narcolettici [Relazione in Atti di Convegno]
Campi, C.; Cipolli, C.; Cicchella, A.; Mattarozzi, K.; Mazzetti, M.; Tuozzi, G.; Bellucci, C.; Vandi, S.; Vignatelli, L; Plazzi, G.

2005 - Memoria semantica durante il sonno REM di pazienti narcolettici [Relazione in Atti di Convegno]
Mazzetti, M.; Campi, C.; Franceschini, C.; Mattarozzi, K.; Tuozzi, G.; Vandi, S.; Vignatelli, L.; Plazzi, G.; Cipolli, C.

2005 - MR spectroscopy study of hypothalamic metabolism in narcolepsy and cluster headache [Capitolo/Saggio]
Lodi, R.; Tonon, C.; Pierangeli, G.; Testa, C.; Plazzi, G.; Cortelli, P.; Montagna, P.; Barbiroli, B.

2005 - NREM sleep alterations in narcolepsy/cataplexy [Articolo su rivista]
Ferri, R.; Miano, S.; Bruni, O.; Vankova, J.; Nevsimalova, S.; Vandi, S.; Montagna, P.; Ferini-Strambi, L.; Plazzi, G.

2005 - Paroxysmal arousal in epilepsy associated with cingulate hyperperfusion [Articolo su rivista]
Vetrugno, R.; Mascalchi, M.; Vella, A.; Della Nave, R.; Provini, F.; Plazzi, G.; Volterrani, D.; Bertelli, P.; Vattimo, A.; Lugaresi, E.; Montagna, P.

2005 - Paroxysmal motor phenomena during sleep: Study on the frequency of parasomnias in patients with nocturnal frontal lobe epilepsy and the relatives [Articolo su rivista]
Bisulli, F.; Naldi, I.; Tinuper, P.; Vignatelli, L.; Ferioli, S.; Pittau, F.; Provini, F.; Plazzi, G.; Vetrugno, R.; Montagna, P.

To verify whether patients with NFLE and their relatives have a higher frequency of parasomnias, in particular arousal disorders, to shed light on the still unknown physiopathological mechanisms underlying NFLE. 358 individuals were interviewed: 26 patients with NFLE (M/F: 13/13), 161 relatives of probands, 20 control subjects and 151 relatives of controls. The following parasomnias were more frequent in the NFLE group: Probands vs controls: bruxism (p &lt; 0.05) and arousal disorders such as sleep walking and sleep terror. Proband relatives vs control relatives: arousal disorders (p = 0.0186) and nightmares (p = 0.002). We confirmed the original hypothesis of a higher frequency of arousal disorders in patients with NFLE and their relatives suggesting a possible common physiopathological mechanism. The study disclosed also two "unexpected" findings: a higher frequency of bruxism in NFLE patients and nightmares in their relatives.

2005 - Predictors of health-related quality of life in patients with narcolepsy [Relazione in Atti di Convegno]
Plazzi, G.; Peschechera, F.; Ingravallo, F.; Montagna, P.; D'Alessandro, R.; Vignatelli, L.

2005 - Propriospinal myoclonus: A motor phenomenon found in restless legs syndrome different from periodic limb movements during sleep [Articolo su rivista]
Vetrugno, R.; Provini, F.; Plazzi, G.; Cortelli, P.; Montagna, P.

2005 - REM sleep behavior disorder in Parkinson's disease: A questionnaire-based study [Articolo su rivista]
Scaglione, C.; Vignatelli, L.; Plazzi, G.; Marchese, R.; Negrotti, A.; Rizzo, G.

2005 - REM sleep behaviour disorder in Parkinson's disease: a questionnaire-based study [Articolo su rivista]
Scaglione, C.; Vignatelli, L.; Plazzi, G.; Marchese, R.; Negrotti, A.; Rizzo, G.; Lopane, G.; Bassein, L.; Maestri, M.; Bernardini, S.; Martinelli, P.; Abbruzzese, G.; Calzetti, S.; Bonuccelli, U.; Provini, F.; Coccagna, G.; Bologna Genova Parma And Pisa Universities Group For The Study Of Rem Sleep Behavior Disorder In Parkinson'S, Disease.

2005 - Semantic memory during REM sleep of narcoleptic patients [Relazione in Atti di Convegno]
Campi, C.; Cipolli, C.; Mazzetti, M.; Mattarozzi, K.; Plazzi, G.; Tuozzi, G.; Vignatelli, L.

2005 - Sleepwalking and other ambulatory behaviours during sleep [Articolo su rivista]
Plazzi, G.; Vetrugno, R.; Provini, F.; Montagna, P.

2004 - Harlequin syndrome: an association with overlap parasomnia [Articolo su rivista]
Lombardi, C; Vetrugno, Roberto; Provini, Federica; Plazzi, Giuseppe; Pierangeli, Giulia; Coccagna, Giorgio; Lugaresi, Elio; Montagna, Pasquale; Cortelli, Pietro

2004 - Health-related quality of life in Italian patients with narcolepsy: the SF-36 health survey [Articolo su rivista]
Vignatelli, L; D'Alessandro, R.; Mosconi, P; FERINI-STRAMBI, L; Guidolin, L; DE VINCENTIIS, A; Plazzi, G.

2004 - In vivo evidence of neuronal loss in the hypothalamus of narcoleptic patients [Articolo su rivista]
Lodi, R.; Tonon, C; Vignatelli, L; Iotti, S; Montagna, P; Barbiroli, B; Plazzi, G

2004 - In vivo evidence of neuronal loss in the hypothalamus of narcoleptic patients [Abstract in Atti di Convegno]
Lodi, Raffaele; Tonon, Caterina; L., Vignatelli; Iotti, Stefano; Montagna, Pasquale; Plazzi, Giuseppe; Barbiroli, Bruno

2004 - Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report [Articolo su rivista]
Barboni, P; Savini, G; Plazzi, G.; Bellan, M; Valentino, Ml; Zanini, M; Montagna, P; Hirano, M; Carelli, V.

2004 - REM sleep behavior disorders in Parkinson's disease and other Parkinsonian disorders [Articolo su rivista]
Plazzi, G.

2004 - Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study [Articolo su rivista]
Vetrugno, R; Provini, F; Cortelli, P; Plazzi, G.; Lotti, Em; Pierangeli, G; Canali, C; Montagna, P.

2004 - Sleep wake-and body core temperature cycles in patients with multiple sclerosis and fatigue [Abstract in Atti di Convegno]
Vetrugno, R.; Stecchi, S.; Scandellari, C.; Provini, F.; Plazzi, G.; Pierangeli, G.; Cortelli, P.; Montagna, P.

2004 - Split-screen synchronized display. A useful video-EEG technique for studying paroxysmal phenomena [Articolo su rivista]
Tinuper, Paolo; Grassi, Carlo; Bisulli, Francesca; Provini, Federica; Plazzi, Giuseppe; Zoni, Elena; Lugaresi, Elio

2004 - Status dissociatus after surgery for tegmental ponto-mesencephalic cavernoma: a state-dependent disorder of motor control during sleep [Articolo su rivista]
Provini, Federica; Vetrugno, Roberto; Pastorelli, F; Lombardi, Carolina; Plazzi, Giuseppe; Marliani, Af; Lugaresi, Elio; Montagna, Pasquale

2003 - Emotional information processing in patients with narcolepsy: A psychophysiologic investigation [Articolo su rivista]
Tucci, V; Stegagno, L; Vandi, S; Ferrillo, F; Palomba, D; Vignatelli, L; Ferini-Strambi, L; Montagna, P; Plazzi, G

2003 - Interobserver reliability of ICSD-R criteria for REM sleep behaviour disorder [Articolo su rivista]
Vignatelli, L; Scaglione, C; Grassi, C; Minguzzi, E; Provini, F; Plazzi, G; Bernardini, S; Negrotti, A; Maestri, M; Marchese, R

2003 - Italian version of the Epworth sleepiness scale: external validity [Articolo su rivista]
Vignatelli, L; Plazzi, G; Barbato, A; Ferini-Strambi, L; Manni, R; Pompei, F; D'Alessandro, R; Ginsen Gruppo Italiano Narcolessia Studio Epidemiologico, Nazionale.

2003 - Pelvic movements as rhythmic motor manifestation associated with restless legs syndrome [Articolo su rivista]
Lombardi, C; Provini, F; Vetrugno, R; Plazzi, G; Lugaresi, E; Montagna, P

2003 - Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health [Articolo su rivista]
Allen, R. P.; Picchietti, D.; Hening, W. A.; Trenkwalder, C.; Walters, A. S.; Montplaisi, J.; Bara-Jimenez, W.; Becker, P.; Bell, G.; Berger, K.; Bliwise, D. L.; Brooks, D.; Consens, F.; Earley, C. J.; Ehrenberg, B. L.; Foley, D.; Murray, C. F.; Garcia-Borreguero, D.; Hallett, M.; Hornyak, M.; Hunt, C. E.; Kushida, C.; Kurth, T.; Launer, L.; Monjan, A.; Nichols, P.; Rye, D. B.; Sharon, D.; Streiner, D. L.; Winkelman, J. W.; Winkelmann, J.; Zak, R.; Adler, C.; Benes, H.; Chokroverty, S.; Ekbom, K.; Frauscher, B.; Hogl, B.; Kryger, M.; Montagna, P.; Oertel, W.; Plazzi, G.; Poceta, J. S.; Silber, M.; Stiasny, K.; Tolosa, E.; Tufik, S.; de Mello, M. T.; Zucconi, M.

Background: Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria. Setting: The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health. Participants: Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales. Objective: To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies. Results: The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups. © 2003 Elsevier Science B.V. All rights reserved.

2003 - Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome [Articolo su rivista]
Walters, As; LeBrocq, C; Dhar, A; Hening, W; Rosen, R; Allen, Rp; Trenkwalder, C; Adler, C; Newman, S; Reiners, C; Aksu, M; Allen, Rp; Buchholz, D; Hening, Wa; Anderson, M; Mosko, S; Ancoli-Israel, S; Jimenez, Wb; Hallett, M; Bassetti, C; Clavadetscher, S; Bliwise, Dl; Gurecki, P; Rye, Db; Broch, Ll; Zak, R; Chokroverty, S; Coccagna, G; Lugaresi, E; Miele, F; Montagna, P; Plazzi, G; Provini, F; de Mello, Mt; Tufik, S; de Weerd, Aw; Rijsman, Rm; Dhar, A; LeBrocq, C; Walters, As; Ehrenberg, B; Eisensehr, I; Ekbom, K; Ljungdahl, A; Garcia-Borreguero, D; Larrosa, O; Hening, Wa; Rosen, R; Walters, As; Hening, Wa; Hirsch, L; Hogl, B; Horiguchi, J; Hornyak, M; Voderholzer, U; Kryger, M; Skomrow, R; Lipinski, Jf; Masood, A; Phillips, B; Oertel, Wh; Stiasny, K; O'Keeffe, S; Oldani, A; Zucconi, M; Ondo, Wg; Picchietti, D; Poceta, Js; Rich, Gb; Scrima, L; Shafor, R; Sharon, D; Silber, M; Smith, R; Trenkwalder, C; Wetter, Tc; Winkelmann, J; Vanek, Z; Wagner, M; Walters, As

2002 - Bilateral paramedian thalamic syndrome: abnormal circadian wake-sleep and autonomic functions [Articolo su rivista]
Montagna, P; Provini, F; Plazzi, G; Vetrugno, R; Gallassi, R; Pierangeli, G; Ragno, M; Cortelli, P; Perani, D

2002 - Does the prion protein gene 129 codon polymorphism influence sleep? Evidence from a fatal familial insomnia kindred [Articolo su rivista]
Plazzi, G; Montagna, P; Beelke, M; Nobili, L; De Carli, F; Cortelli, P; Vandi, S; Avoni, P; Tinuper, P; Gambetti, P; Lugaresi, E; Ferrillo, F

2002 - Excessive fragmentary hypnic myoclonus: clinical and neurophysiological findings [Articolo su rivista]
Vetrugno, R; Plazzi, G; Provini, F; Liguori, R; Lugaresi, E; Montagna, P

2002 - Familial nocturnal facio-mandibular myoclonus mimicking sleep bruxism [Articolo su rivista]
Vetrugno, R; Provini, F; Plazzi, G; Lombardi, C; Liguori, R; Lugaresi, E; Montagna, P

2002 - ICSD diagnostic criteria for narcolepsy: Interobserver reliability [Articolo su rivista]
Vignatelli, L; Plazzi, G; Bassein, L; Barbato, A; De Vincentiis, A; Lugaresi, E; D'Alessandro, R; Gin-Se, N. Gruppo Italiano Narcolessia- Studio Epidemiologico Nazionale.

2002 - Motor pattern of periodic limb movements in sleep in idiopathic RLS patients [Articolo su rivista]
G., Plazzi; R., Vetrugno; Meletti, Stefano; F., Provini

Objective: Periodic limb movements in sleep (PLMS) are recurrent sleep-related movements that often occur in association with restless legs syndrome (RLS). The purpose of the present study was to examine the pathophysiology of PLMS in patients with idiopathic RLS.Methods: Ten patients with idiopathic RLS who were medication-free or who had withdrawn from medication at least 2 weeks prior to the study underwent an extensive neurophysiological investigation that included nocturnal video-polysomnographic recording (VPSG), EMG recording, and the Multiple Sleep Latency Test (MSLT). Sleep efficiency and PLMS index were calculated during VPSG.Results: All patients had an increased PLMS index, decreased sleep efficiency, and a pathological MSLT score. Leg muscles were the first to be activated, often with alternation of side, and no constant recruitment pattern could be found from one episode of PLMS to another, even in the same patient. No ordinate caudal or rostral spread of the EMG activity was observed.Conclusions: The results suggest that there are different, independent, and unsynchronized generators for PLMS. The direct participation of the cerebral cortex in the origin of PLMS is unlikely, suggesting that abnormal spinal cord hyperexcitability may act as the primary cause of PLMS, triggered by unidentified sleep-related factors.

2002 - Polysomnographic study of sleeplessness and oneiricisms in the alcohol withdrawal syndrome [Articolo su rivista]
Plazzi, G.; Montagna, P.; Meletti, Stefano; Lugaresi, E.

We describe a polysomnographic observation of the acute phase of the alcohol withdrawal syndrome, characterized by an alteration of the sleep–wake cycle and by the absence of non-rapid eye movement sleep. An atypical transitional state between rapid eye movement sleep and wake with hallucinations and enacting-dream behaviors represented the sole sleep pattern. Analogies of alcohol withdrawal syndrome with fatal familial insomnia and Morvan’s fibrillary chorea suggest a common pathophysiological mechanism in these conditions.

2002 - Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis [Articolo su rivista]
Plazzi, G; Montagna, P.

2001 - Absence of sleep EEG markers in fatal familial insomnia healthy carriers: a spectral analysis study [Articolo su rivista]
Ferrillo, F; Plazzi, G; Nobili, L; Beelke, M; De Carli, F; Cortelli, P; Tinuper, P; Avoni, P; Vandi, S; Gambetti, P; Lugaresi, E; Montagna, P

2001 - Catathrenia (nocturnal groaning): a new type of parasomnia [Articolo su rivista]
Vetrugno, R; Provini, F; Plazzi, G; Vignatelli, L; Lugaresi, E; Montagna, P.

2001 - Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels [Articolo su rivista]
Liguori, R; Vincent, A; Clover, L; Avoni, P; Plazzi, G; Cortelli, P; Baruzzi, A; Carey, T; Gambetti, P; Lugaresi, E; Montagna, P.

2001 - Motor pattern of periodic limb movements during sleep [Articolo su rivista]
Provini, F.; Vetrugno, R.; Meletti, Stefano; Plazzi, G.; Solieri, L.; Lugaresi, E.; Coccagna, G.; Montagna, P.

Background: The pathophysiology of periodic limb movements in sleep (PLMS) in restless legs syndrome (RLS) is unclear. Objective: The authors neurophysiologically investigated PLMS in patients with idiopathic RLS in order to obtain information on the origin and pathophysiology of the movements. Methods: Ten patients with idiopathic RLS underwent electromyography with nerve conduction velocity (EMG-CV), somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS), nocturnal videopolysomnography, and multiple sleep latency test. The authors analyzed 100 consecutive PLMS for each patient to determine how frequently each muscle was involved in the PLMS; how frequently EMG activity started in a given muscle; and the time delay and pattern of activation between the first and theother activated muscles. Results: EMG-CV, SEPs, and TMS findings were all normal; in PLMS, leg muscles were thosemore frequently involved, often with alternation of side. Axial muscles were rarely and upper limb muscles sometimesinvolved. The tibialis anterior was the most frequent starting muscle. There was no constant recruitment pattern from onePLMS episode to another, even in the same patient. There was no ordinate caudal or rostral spread of the EMG activity.Conclusion: The recruitment pattern indicates the engagement of different, independent, and sometimes unsynchronizedgenerators for each PLMS. The authors hypothesize an abnormal hyperexcitability along the entire spinal cord, especiallyits lumbosacral and cervical segments, as the primary cause of PLMS, triggered by sleep-related factors located at asupraspinal but still unresolved level.

2001 - Propriospinal myoclonus at the sleep-wake transition: a new type of parasomnia [Articolo su rivista]
R., Vetrugno; F., Provini; Meletti, Stefano; G., Plazzi; R., Liguori; P., Cortelli; E., Lugaresi; P., Montagna

STUDY OBJECTIVES: To describe the clinical, neurophysiological, and polysomnographic characteristics of propriospinal myoclonus (PSM) at the sleep-wake transition. DESIGN: Patients referred for insomnia due to myoclonic activity arising during relaxed wakefulness preceding sleep, or complaining of muscular jerks also during intrasleep wakefulness and upon awakening in the morning were considered. SETTING: All patients underwent EEG-EMG recordings during wakefulness and night sleep. Back-averaging of the EEG activity preceding the jerks was performed. Somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS) and spinal and cranial MRI were also done. PARTICIPANTS: Four patients were studied all affected with involuntary jerks arising when falling asleep, and one with jerks also during sleep and upon awakening in the morning. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Polysomnographic investigations revealed jerks arising during the sleep-wake transition period. Myoclonic activity was neurophysiologically documented to be of the propriospinal type. SEPs, TMS and MRI were normal CONCLUSIONS: PSM may have a peculiar relationship with the state of vigilance and represent a sleep-wake transition disorder. In this regard we consider PSM a new type of parasomnia.

2001 - Reflex epileptic seizures: The Videoteque Commission of the Italian League Against Epilepsy (LICE) [Articolo su rivista]
Tinuper, P.; Canevini, M. P.; Fusco, L.; Giallonardo, M. T.; Guerrini, R.; Munari, C.; Plazzi, G.; Rubboli, G.; Vigevano, F.

2001 - Validation of symptoms related to excessive daytime sleepiness [Articolo su rivista]
Rinaldi, R; Vignatelli, L; D'Alessandro, R; Bassein, L; Sforza, E; Plazzi, G; Provini, F; Lugaresi, E.

2000 - Focal myoclonus and propriospinal propagation [Articolo su rivista]
Vetrugno, R; Provini, F; Plazzi, G; Valentino, Ml; Liguori, R; Lugaresi, E; Montagna, P.

2000 - From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy [Articolo su rivista]
Provini, F; Plazzi, G; Lugaresi, E.

2000 - Nocturnal frontal lobe epilepsy: a wide spectrum of seizures [Articolo su rivista]
Provini, F; Montagna, P; Plazzi, G; Lugaresi, E.

2000 - Sleep and sleepiness in Parkinson's disease [Articolo su rivista]
Plazzi, G.

2000 - Sleep stage-related changes in sympathetic sudomotor and vasomotor skin responses in man [Articolo su rivista]
Liguori, R; Donadio, V; Foschini, E; DI STASI, V; Plazzi, G; Lugaresi, E; Montagna, P.

2000 - The wide clinical spectrum of nocturnal frontal lobe epilepsy [Articolo su rivista]
Provini, F; Plazzi, G; Montagna, P; Lugaresi, E.

1999 - Bilateral centrotemporal spikes triggered by blinking: an unusual form of sensory input with related cortical EEG activity [Articolo su rivista]
Vetrugno, R.; Meletti, Stefano; Plazzi, G.; Posar, A.; Santucci, M.; Rossi, P. G.; Lugaresi, E.; Liguori, R.

Objective: To investigate the morphology, scalp topography and temporal relationship with orbicularis oculi muscle contraction ofbilateral blink related spikes (BRS) in a 7-year-old boy with chromosomopathy, mild mental retardation and left spontaneous centrotemporal spikes (SS).Methods: The patient underwent video-polygraphic recordings with off-line analysis of SS and BRS by means of spike-averaging and orbicularis oculi contraction-locked averaging techniques respectively. EEG activity related to reflex blinking (evoked by glabellar tapping) was also studied.Results: SS and BRS presented the same morphology, characterised by four peaks (P1, N1, P2, N2). SS were located over the left centroparietal regions, while BRS were placed over both left and right centrotemporoparietal regions and constantly followed the contraction of orbicularis oculi with overlapping peak latencies over C3 and C4 electrodes (P1 72 ms; N1 115 ms; P2 164 ms; N2 236 ms). Refex blinking evoked a small waveform with the same features as BRS.Conclusions: Our fndings suggest that both involuntary and reflex blinking can act as a form of sensory stimulation probably engaging similar nervous pathways and cortical sources in generating EEG abnormalities: the trigeminal system.

1999 - Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases [Articolo su rivista]
Provini, F; Plazzi, G; Tinuper, P; Vandi, S; Lugaresi, E; Montagna, P.

1998 - Autosomal dominant nocturnal frontal-lobe epilepsy: Genetic heterogeneity and evidence for a second locus at 15q24 [Articolo su rivista]
Phillips, Ha; Scheffer, Ie; Crossland, Km; Bhatia, Kp; Fish, Dr; Marsden, Cd; Howell, Sjl; Stephenson, Jbp; Tolmie, J; Plazzi, G; Eeg-Olofsson, O; Singh, R; Lopes-Cendes, I; Andermann, E; Andermann, F; Berkovic, Sf; Mulley, Jc

1998 - Clinical features of fatal familial insomnia: Phenotypic variability in relation to a polymorphism at codon 129 of the prion protein gene [Articolo su rivista]
Montagna, P; Cortelli, P; Avoni, P; Tinuper, P; Plazzi, G; Gallassi, R; Portaluppi, F; Julien, J; Vital, C; Delisle, Mb; Gambetti, P; Lugaresi, E

1998 - Endozepine stupor - Recurring stupor linked to endozepine-4 accumulation [Articolo su rivista]
Lugaresi, E; Montagna, P; Tinuper, P; Plazzi, G; Gallassi, R; Wang, Tcl; Markey, Sp; Rothstein, Jd

1998 - Pontine lesions in idiopathic narcolepsy - Reply [Articolo su rivista]
Plazzi, G; Montagna, P; Provini, F; Lugaresi, E; Bizzi, A; Cohen, M

1998 - REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure [Articolo su rivista]
Plazzi, G; Cortelli, P; Montagna, P; De Monte, A; Corsini, R; Contin, M; Provini, F; Pierangeli, G; Lugaresi, E

1998 - Sudden arousals from slow-wave sleep and panic disorder [Articolo su rivista]
Plazzi, G; Montagna, P; Provini, F; Tinuper, P; Lugaresi, E

1998 - Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor [Articolo su rivista]
Lugaresi, E; Montagna, P; Tinuper, P; Plazzi, G; Gallassi, R.

1997 - Alterations of sleep and circadian blood pressure profile [Articolo su rivista]
Portaluppi, F; Cortelli, P; Provini, F; Plazzi, G; Manfredini, R; Lugaresi, E

1997 - Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [Articolo su rivista]
Plazzi, G; Montagna, P; Tinuper, P; Cerullo, A; Provini, F; Lugaresi, E

1997 - Endozepine stupor in children [Articolo su rivista]
Soriani, S; Carrozzi, M; Decarlo, L; Plazzi, G; Provini, F; Rothstein, Jd; Tinuper, P; Bouquet, F; Lugaresi, E; Montagna, P

1997 - Genetic heterogeneity in autosomal dominant nocturnal frontal lobe epilepsy [Articolo su rivista]
Mochi, M; Provini, F; Plazzi, G; Corsini, R; Farnedi, F; Tinuper, P; Valentino, Ml; Lugaresi, E; Montagna, P

1997 - Heavy snorer disease: from snoring to the sleep apnea syndrome - an overview [Articolo su rivista]
Lugaresi, E; Plazzi, G

1997 - Motor disorders in sleep [Articolo su rivista]
Montagna, P; Lugaresi, E; Plazzi, G

1997 - Motor overactivity and loss of motor circadian rhythm in fatal familial insomnia: An actigraphic study [Articolo su rivista]
Plazzi, G; Schutz, Y; Cortelli, P; Provini, F; Avoni, P; Heikkila, E; Tinuper, P; Solieri, L; Lugaresi, E; Montagna, P

1997 - Propriospinal myoclonus: Clinical and polygraphic features in 5 cases [Articolo su rivista]
Montagna, P.; Plazzi, G.; Liguori, R.; Meletti, Stefano; Provmi, F.; Cevoli, S.; Lugaresi, E.

Propriospinal Myoclonus (PSM) is characterized by jerks arising within the cord and propagating rostrally and caudally at low velocity, probably along propnospmal pathways intrinsic to the cord. In the last years we have encountered 5 males aged between 41 to 73 years displaying the clinical and polygraphic features of PSM PSM had set in all without any recognizable trigger, and neurological examination and MRI of cord and brain were normal in all except one patient who had an arachnoid cyst at the level of the T9 left root. EMG showed that the jerks arose in spinally innervated muscles, usually the thoracic or lumbar segments; the jerks were thereafter propagated to rostral and caudal muscles at velocities of 3 to 16 m/s, according to a propriospinal pattern of propagation. Polygraphic studies showed that in 4 cases the jerks occurred quasirhythmically only during periods of relaxed wakefulness, when EEG alpha activity spread to anterior regions. Any mental activation and sleep inhibited the PSM. In the 5th case, some features of the restless legs syndrome were found, and the jerks lasted into light sleep. PSM responded partially to clonazepam or tramadol. PSM is a peculiar movement disorder arising in the spinal cord but subjected to supraspinal influences during the various wake and sleep stages. It may represent a cause of severe insomnia.

1997 - Propriospinal myoclonus upon relaxation and drowsiness: A cause of severe insomnia [Articolo su rivista]
Montagna, P; Provini, F; Plazzi, G; Liguori, R; Lugaresi, E

1997 - REM sleep behavior disorders in multiple system atrophy [Articolo su rivista]
Plazzi, G; Corsini, R; Provini, F; Pierangeli, G; Martinelli, P; Montagna, P; Lugaresi, E; Cortelli, P.

1997 - Undiagnosed sleep-disordered breathing among male nondippers with essential hypertension [Articolo su rivista]
Portaluppi, F; Provini, F; Cortelli, P; Plazzi, G; Bertozzi, N; Manfredini, R; Fersini, C; Lugaresi, E

1996 - Blood pressure rhythms in sleep disorders and dysautonomia [Articolo su rivista]
Cortelli, P; Pierangeli, G; Provini, F; Plazzi, G; Lugaresi, E

1996 - Celiac disease, epilepsy, and occipital calcifications: Histopathological study and clinical outcome [Articolo su rivista]
Tinuper, P; Plazzi, G; Provini, F; Cerullo, A; Gambarelli, D; Pellissier, Jf; Lugaresi, E

1996 - Partial epilepsy of long duration: Changing semiology with age [Articolo su rivista]
Tinuper, P; Provini, F; Marini, C; Cerullo, A; Plazzi, G; Avoni, P; Baruzzi, A

1996 - Pontine lesions in idiopathic narcolepsy [Articolo su rivista]
Plazzi, G; Montagna, P; Provini, F; Bizzi, A; Cohen, M; Lugaresi, E.

Montagna, P; Plazzi, G; Cortelli, P; Carelli, V; Lugaresi, E; Barboni, P; Fiocchi, M

Tinuper, P; Cerullo, A; Riva, R; Marini, C; Provini, F; Plazzi, G; Baruzzi, A; Lugaresi, E

1995 - EPILEPTIC NOCTURNAL WANDERINGS [Articolo su rivista]
Plazzi, G; Tinuper, P; Montagna, P; Provini, F; Lugaresi, E

1995 - Idiopathic recurring stupor [Articolo su rivista]
Goldman, H.; Tinuper, P.; Montagna, P.; Plazzi, G.; Lugaresi, E.

1995 - IDIOPATHIC RECURRING STUPOR - REPLY [Articolo su rivista]
Tinuper, P; Montagna, P; Plazzi, G; Lugaresi, E

Montagna, P; Sforza, E; Tinuper, P; Provini, F; Plazzi, G; Cortelli, P; Schoch, P; Rothstein, Jd; Lugaresi, E

Tinuper, P; Montagna, P; Plazzi, G; Lugaresi, E

Tinuper, P; Plazzi, G; Monari, L; Sangiorgi, S; Pellissier, Jf; Cerullo, A; Provini, F; Capellari, S; Baruzzi, A; Lugaresi, E; Montagna, P

1994 - IDIOPATHIC RECURRING STUPOR [Articolo su rivista]
Tinuper, P; Montagna, P; Plazzi, G; Avoni, P; Cerullo, A; Cortelli, P; Sforza, E; Bonetti, Ep; Schoch, P; Rothstein, Jd; Guidotti, A; Lugaresi, E

Plazzi, G; Tinuper, P; Cerullo, A; Provini, F; Lugaresi, E

1994 - Vigabatrin and psychosis [Articolo su rivista]
Plazzi, Giuseppe

Use of Vigabatrin (GVG) in the treatment of severe refractory epilepsy has been associated with sporadic development of psychosis. Two women with drug-resistant complex partial seizures and no previous history of psychosis developed a psychotic state following GVG treatment, during which they did not present seizures and EEG was improved or normal. The mechanism of this behaviour change is unclear as is the nature of the association between GVG treatment and psychosis.

Rothstein, Jd; Guidotti, A; Tinuper, P; Cortelli, P; Avoni, P; Plazzi, G; Lugaresi, E; Schoch, P; Montagna, P

Tinuper, P; Plazzi, G; Provini, F; Cerullo, A; Leonardi, M; Agati, R; Righini, A; Montagna, P

1991 - Status epilepticus induced by eye-closure [Articolo su rivista]
Plazzi, Giuseppe

A 20-year-old girl manifested EEG generalized epileptic discharges triggered by every eye-closure in light and darkness. These anomalies were always associated with clonic jerks of the eyelids and lasted as long as eye-closure was maintained. No photosensitivity was observed.