European-guideline-and-expert-statements-on-the-management-of-narcolepsy.pdf

| Accepted: 21 April 2021 DOI: 10.1111/jsr.13387 GUIDELINES European guideline and expert statements on the management of narcolepsy in adults and children Claudio L. A. Bassetti1 | Ulf Kallweit2 | Luca Vignatelli3 | Giuseppe Plazzi3,4 | 5,6 3 7,8 9 Michel Lecendreux | Elisa Baldin | Leja Dolenc-Groselj | Poul Jennum | Ramin Khatami1,10 | Mauro Manconi1,11 | Geert Mayer12,13 | Markku Partinen14 | 15 16 17 18 Thomas Pollmächer | Paul Reading | Joan Santamaria | Karel Sonka | Yves Dauvilliers19 | Gert J. Lammers20,21 1 Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland 2 Center for Narcolepsy/Hypersomnias, Clin. Sleep and Neuroimmunology, Institute of Immunology, University Witten/Herdecke, Witten, Germany 3 IRCCS, Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy 4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy 5 AP-HP, Pediatric Sleep Center, CHU Robert-Debré, Paris, France 6 National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), Paris, France 7 Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 8 Department of Neurology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 9 Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Faculty of Health Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 10 Center of Sleep Medicine, Sleep Research and Epileptology, Clinic Barmelweid, Barmelweid, Switzerland 11 Sleep Center, Faculty of Biomedical Sciences, Neurocenter of Southern Switzerland, Università della Svizzera Italiana, Lugano, Switzerland 12 Neurology Department, Hephata Klinik, Schwalmstadt, Germany 13 Department of Neurology, Philipps-Universität Marburg, Marburg, Germany 14 Department of Clinial Neurosciences, Clinicum, Helsinki Sleep Clinic, Vitalmed Research Center, Terveystalo Biobank and Clinical Research, University of Helsinki, Helsinki, Finland 15 Center for Mental Health, Klinikum Ingolstadt, Ingolstadt, Germany 16 Department of Neurology, James Cook University Hospital, Middlesbrough, UK 17 Neurology Service, Hospital Clínic of Barcelona, Barcelona, Spain 18 Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 19 National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, INM INSERM, Montpellier, France 20 Sleep Wake Centre SEIN, Heemstede, The Netherlands 21 Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands Bassetti and Kallweit shared first authorship. Dauvilliers and Lammers shared last authorship. Bassetti, Kallweit, Dauvilliers and Lammers contributed equally. A joint European guideline from the European Academy of Neurology, the European Sleep Research Society and the European Narcolepsy Network. This article is co-published by the European Journal of Neurology and the Journal of Sleep Research. [Correction added on 12 July 2021, after first online publication: The copyright line was changed.] This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Academy of Neurology and European Sleep Research Society J Sleep Res. 2021;30:e13387. https://doi.org/10.1111/jsr.13387 wileyonlinelibrary.com/journal/jsr | 1 of 17 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 20 April 2021 | Correspondence Claudio L.A. Bassetti, Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. Ulf Kallweit, Center for Narcolepsy, Clin. Sleep and Neuroimmunology, Institute of Immunology, University Witten/Herdecke, Witten, Germany. Email: [email protected] (CLAB); [email protected] (UK) Funding information European Academy of Neurology (EAN), European Sleep Research Society (ESRS), European Narcolepsy Network (EU-NN). BASSETTI et al. Summary 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. KEYWORDS cataplexy, European, guideline, management, narcolepsy 1 | I NTRO D U C TI O N : BAC KG RO U N D A N D S CO PE 1.1 | Clinical need for a guideline Worldwide prevalence estimates suggest that approximately 25–50 persons out of 100,000 are affected (Oyahon et al., 2002; Partinen & Kronholm, 2017). Some recent studies indicate, that narcolepsy may be less frequent (Tió et al., 2018). Narcolepsy potentially affects every aspect of daily life with considerable personal, Narcolepsy is a disabling hypothalamic disorder that presents with a social and economic consequences. As a result, quality of life mea- variety of sleep-wake and other symptoms. Excessive daytime sleep- sures of both patients and their families are significantly reduced iness (EDS) is usually the most troublesome feature although signifi- (Dodel et al., 2007; Jennum et al., 2012). Current treatments include cantly fragmented and disturbed nighttime sleep (DNS) is common non- pharmacological and pharmacological approaches (Bassetti with phenomena including sleep paralysis and hallucinatory experi- et al., 2019; Dauvilliers et al., 2017; Kallweit & Bassetti, 2017). ences around sleep-wake transitions (hypnagogic and hypnopompic Treatment guidelines for narcolepsy were first published in hallucinations [Bassetti et al., 2019; Yoss & Daly, 1957]). Whereas Europe in 2006 (Billiard, Bassetti et al., 2006) and in the USA in 2007 narcolepsy with typical cataplexy (type 1 narcolepsy, NT1) is con- (Morgenthaler et al., 2007). Criteria for diagnosing narcolepsy into sidered a distinct entity, associated with hypocretin deficiency, nar- types 1 and 2 (NT1 and NT2) were revised in 2014 by the American colepsy without cataplexy (type 2 narcolepsy, NT2) is less clearly Academy of Sleep Medicine. A recent paper addressed the limita- defined and when diagnosed following the current diagnostic crite- tions of the current International Classification of Sleep Disorders ria a heterogeneous disorder (Bassetti et al., 2019). Although the precise etiology of narcolepsy is unknown, most 3 (ICSD-3) diagnostic criteria and made suggestions for future improvements (Lammers et al., 2020). evidence suggests it is usually a sporadic acquired immune-mediated Since 2006, there has been considerable developments in our condition that develops in people who are genetically predisposed understanding of both the etiopathology and clinical characteristics (Latorre et al., 2018; Liblau et al., 2015; Partinen et al., 2014; Yoss in narcolepsy. Furthermore, several new drugs have become avail- & Daly, 1957). able. This has prompted the European Academy of Neurology (EAN), 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 of 17 3 of 17 European Sleep Research Society (ESRS) and European Narcolepsy co-chairs and circulated to the rest of the task force working group, Network (EU- NN) to join forces to provide up- to- date, evidence- prior to rating their relative importance for clinical decision-making. based recommendations for narcolepsy treatments. Patient represen- Outcome prioritization was undertaken using a 9-point Likert scale tatives have been included in the task force, expanding its perspective. and grouped into three categories (1–3, outcome of low importance; 4–6, outcome important but not critical for decision making and 7–9, 1.2 | Scope outcome critical for decision making). Only outcomes graded as critical or important according to expert opinion were subsequently analysed. Finally, 10 key questions were formulated and organized into five sec- This guideline focuses on people of any age with a specific diagnosis tions (see below). The Patients–Intervention–Comparator–Outcome of narcolepsy (NT1 and NT2). It does not address disorders in the (PICO) framework was then used to formulate sub-questions, integral narcoleptic ‘borderland’ such as idiopathic hypersomnia or any other to the search strategies and draft recommendations. For the exact condition causing EDS. Symptomatic treatments of EDS, cataplexy, wording of the PICO questions and additional information, please see and the predominantly nocturnal symptoms of narcolepsy (DNS, the Supporting Information Appendix S1 and also see below. sleep paralysis, sleep-related hallucinations) are assessed, including first-line, second-line and combination therapies. It also evaluates pharmacological treatments that are potentially disease modifying as well as therapies for a variety of comorbid conditions. The lat- 2.1.1 | PICOs classified into groups and as individual questions ter include psychiatric symptoms and fatigue (Droogleever Fortuyn et al., 2012), obesity, sleep-disordered breathing, rapid eye move- Group/Topic ment sleep behavior disorder (RBD), restless legs syndrome and pe- 1. Are there disease- modifying pharmacological treatments for riodic limb movements (RLS/PLMS). Where appropriate, evaluations narcolepsy that can restore hypocretin transmission or reverse for adults and children are described separately. For some clinical situations, expert statements are included. Patients’ view on the management of narcolepsy is also included in a special section. the disease process? 2. Can non- pharmacological treatments improve symptoms of narcolepsy? 3. Can pharmacological treatments improve the symptoms of narco- 2 | M E TH O D S lepsy in adults? 4. Can any non-pharmacological or pharmacological treatments improve comorbidities and/or quality of life measures in patients The EAN, the ESRS and the EU-NN nominated 18 experts in narcolepsy from 11 European countries to form a task force. Four patient representatives were elected by a patient assembly during the with narcolepsy? 5. Can pharmacological treatments improve the symptoms of narcolepsy in children? European Narcolepsy Day 2018 and were subsequently added the task force to provide an opinion statement around key areas of clinical management and research outcomes. Within the task force, 10 2.2 | Search strategy working sub-groups were appointed, each consisting of two experts responsible for one clinical question. This guideline was developed in accordance with the recom- Published studies were identified from the National Library of Medicine's MEDLINE database, Elsevier's Embase database and the mendations of the GRADE Working Group (https://www.grade Cochrane Central Register of Controlled Trials by means of specific workinggroup.org/) and in line with the 2015 practical recommen- search strategies using a combination of exploded terms and free dations for the process of proposing, planning and writing a neu- text, focusing on narcolepsy and treatments for narcolepsy. The rological management guideline by EAN task forces (Leone et al., strategy used for MEDLINE was translated to other databases. No 2015). For the procedures in detail, see the Supplement Appendix language or date of publication restrictions was applied. Rarely, if S1 online. studies had distinguished between the differing types of narcolepsy, Following preparatory talks in 2016, the task force was estab- notably NT1 and NT2, this is mentioned in the text. The literature lished after a signed agreement between the three societies in 2017. search was performed between July and October 2018 and finally The guideline production was finalized in September 2020. updated in July 2020. For pharmacological treatments, another update was performed in October 2020. 2.1 | Guideline questions 2.3 | Data synthesis As an initial step, key questions and potential outcomes essential for the clinical management of patients with narcolepsy were identified. A descriptive summary of the included studies with details of An explicit list of outcomes for each question was proposed by the study design, number and characteristics of enrolled patients, 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | BASSETTI et al. | BASSETTI et al. intervention(s) and comparator(s), outcome measures and results of wakefulness test in few cases of NT1) and cataplexy (in animals) was first provided in tables and then presented in Summary of (Yukitake et al., 2019). Findings tables by individual outcome and intervention. 2.4 | Grading the quality of the evidence and developing recommendations 3.1.2 | Group 2 Question(s) — Non- pharmacological management PICO 2 The guideline was developed following the GRADE approach. What is the clinical evidence of non-pharmacological treatments in Overall quality of evidence for each outcome was assessed by the the management of narcolepsy? methodology sub-group (EB, LV). For further details, please see the Method chapters found in the Supporting Information Appendix S1 online. Introduction Non- pharmacological management of symptom control in narcolepsy should always be considered first. Non-pharmacological approaches increase patient involvement and enhance self-empowerment. 3 | R E S U LT S Factors such as age, gender, profession, specific life situations and comorbidities will influence the potential for using non-pharmacological strategies. In some situations where medication is considered inap- A total of 10,241 references were evaluated for possible inclusion. propriate such as pregnancy or potentially in early childhood, non- Full texts of 308 studies were assessed with 155 meeting the inclu- pharmacological management approaches are mandatory. sion criteria. A descriptive summary of the whole process and find- Recommendations –We recommend planned daytime naps to im- ings is provided in the Supporting Information Appendix S1. Results prove immediate subjective and objective sleepiness both in drug naïve of the literature search and overall quality of evidence for individual narcolepsy patients and in those taking stimulant medication, at any PICOs are also provided in the Supporting Information Appendix age. S1. References indicated with an asterisk (*) refer to the Supporting See Table S2. Information. Although available evidence on non- pharmacological treatment other than scheduled napping is low, the concept of such ap- 3.1 | Search questions proaches is strongly supported as they promote better acceptance of the disease and compliance. Informed scientific knowledge of narcolepsy in any patient group is mandatory, including disease 3.1.1 | Group 1 Question(s)—Disease modification mechanisms and treatment options. Attempts to implement a fixed schedule for nocturnal sleep and daytime activities with short PICO 1 scheduled naps during the day are considered important. A general What is the clinical evidence for the efficacy of disease-modifying healthy lifestyle including regular physical activity and weight con- treatments for the remission or improvement of narcolepsy? trol are also considered important and might be expected to result Introduction not only in an improvement of symptom control but also enhanced Preventing total hypocretin neuron loss by an immunomodula- patient-empowerment. For many patients, joining a patients’ orga- tory treatment close to disease onset or in highly selected patients nization turns out to be of great help as a source of information, or hypocretin replacement therapy (hypocretin, hypocretin ana- exchange and support. logues, hypocretin receptor agonists) may be considered as potential treatment strategy. Recommendations –Among the disease modifying treatments evaluated none is recommended. Future directions/outlook Non- pharmacological treatment is considered important and forms an initial foundation for managing narcolepsy. Patients often have a special interest in non- pharmacological approaches (see See Table S1. below) although available scientific evidence for efficacy is very Future directions/outlook limited. Studies evaluating the potentially positive impact of special Specific monoclonal antibody therapies might represent a thera- diet, light therapy or exercise programs are needed. peutic option in the future to prevent or slow hypocretin neuron loss. The potential for severe side effects of such immune-modulatory treatments and uncertainties when to start therapy will require well- designed studies in carefully selected narcolepsy populations. 3.1.3 | Group 3 Question(s)—Symptomatic pharmacological treatments in adults Selective hypocretin receptor agonists are a promising new class of drugs. Recently pilot trials on the hypocretin receptor agonist General comment: The overall goal of most symptomatic treat- TAK-994 (animal data) and TAK-925 (adults with NT1) indicated a sig- ments should focus on improving the sleep-wake cycle of narco- nificant improvement of EDS (with normalization of the maintenance leptic patients with particular attention on daytime performance. 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 17 5 of 17 Improving EDS and reducing cataplexy are typically most important. PICO 4 Treatment goals and choice of treatments should take into consid- What is the clinical evidence for efficacy of pharmacological treat- eration an individual's pattern of symptoms, preferences and exist- ment of moderate to severe cataplexy? Is there a difference in ef- ing co-morbidities. ficacy between different drugs? What is the benefit-to-risk ratio of treatments? PICO 3 Introduction What is the clinical evidence for the efficacy of pharmacological Cataplexy is a pathognomonic symptom of narcolepsy, which treatment of EDS and associated features? Is there a difference is reported by 60%–70% of all narcolepsy patients (Bassetti et al., in efficacy between different wake-promoting drugs? What is the 2019). In moderate to severe cataplexy, pharmacological treatment benefit-to-risk ratio of treatments? is usually warranted. Introduction Recommendations Excessive daytime sleepiness is usually the most prominent dis- See Figure 1 and Table S4. abling symptom in patients with narcolepsy (Bassetti et al., 2019). EDS can present with different phenotypes including sleep attacks, involuntary napping, automatic behaviors, an excessive need for sleep (hypersomnia sensu strictu), difficulty sustaining attention, and Due to a lack of data, comparison of efficacy of different drugs is not possible. Future directions/outlook Randomized clinical trials (RCTs) comparing serotonin– cognitive dysfunction. An improvement in EDS is usually assessed by norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine clinical history or questionnaires. Objective testing such as multiple against sodium oxybate to assess the specific benefit-to-risk ratio sleep latency test (often used for diagnosis) and the maintenance of should be considered. New drugs such as hypocretin receptor ago- wakefulness test (often used to document treatment response) may nists may represent a valid option for future treatment of cataplexy. provide useful information. Based on several randomized controlled trials (RCTs) and clin- PICO 5 ical experience, there is clear evidence that a number of wake- What is the clinical evidence for efficacy of pharmacological treat- promoting agents and sodium oxybate improve EDS. Treatment ment for moderate to severe DNS? Is there a difference in effi- choices may change over time and be affected by factors such cacy between different drugs? What is the benefit-to-risk ratio of as age, lifestyle, severity, tolerance and comorbidities. Clinicians treatments? should therefore regularly reassess treatment efficacy and safety Introduction during follow-up visits. Data on the long-term efficacy and safety Nocturnal sleep is significantly disturbed in at least 65% of pa- are limited. A recent 1-year open-label single-arm pragmatic study tients with narcolepsy. Disruption of sleep maintenance is the most supports the long-term safety and efficacy of pitolisant for treat- common problem with recurring short and long wake periods. Sleep ment of EDS in patients with NT1 and NT2 (Dauvilliers et al., 2019). onset is usually unaffected. Over 24 h, the total sleep time of a nar- However, one-third of patients stopped the medication due to lack coleptic person is often within normal limits. The extent of sleep of efficacy or side effects. fragmentation potentially in association with vivid dreaming and/or A recent trial performed over 24 months (Schinkelshoek et al., nightmares, RBD but also RLS/PLMS and sleep-disordered breath- 2019) reported a reduction in body mass index in NT1 patients treated ing can adversely influence daytime functioning and EDS prompting with sodium oxybate, confirming previous clinical observations. many patients to seek treatment for improving DNS. Stimulants (methylphenidate, modafinil, amphetamines, and sol- Recommendations riamfetol) may increase heart rate and blood pressure with risk of See Figure 1 and Table S5. hypertension. These potential side effects require careful monitor- Future directions/outlook ing and may lead to specific management strategies (Bosco et al., 2018). Different compositions or formulations of sodium oxybate e.g., low-salt, and long acting formulations may have an additional impact Recommendations on improvement of DNS and are studied in RCTs. There is a need for See Figure 1 and Table S3. more RCTs assessing DNS in narcolepsy both for existing drugs and The lack of head-to-head studies makes comparisons of efficacy newer compounds. between different stimulants/wake-promoting drugs difficult. The alerting effects of stimulating antidepressants were not evaluated PICO 6 as clinical experience suggests any impact on EDS in narcolepsy is at What is the clinical evidence for efficacy of the pharmacological treat- best minor. Antidepressants should not be considered as treatments ment of moderate to severe sleep paralysis and hypnagogic/hypnop- for EDS. ompic hallucinations? What is the benefit-to-risk ratio of treatments? Future directions/outlook New compounds including novel histamine 3 receptor inverse agonists and hypocretin receptor agonists may soon become available for treatment of EDS in NT1 and NT2. Is there a difference in efficacy between different drugs? Introduction Sleep paralysis and hypnagogic/hypnopompic hallucinations are reported by approximately 50% of patients with narcolepsy (Bassetti 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | BASSETTI et al. | BASSETTI et al. et al., 2019). No RCTs focused primarily on these symptoms and See Table S7. none were appropriately powered to detect efficacy of treatments. Future directions/outlook Recommendations See Figure 1 and Table S6. Studies evaluating effects of treatments for other sleep disorders in narcolepsy are needed. Future directions/outlook There is a need for specific trials on the impact of compounds in- PICO 9 cluding antidepressants and sodium oxybate on sleep paralysis and What is the clinical evidence of efficacy for treatments on meas- hypnagogic/hypnopompic hallucinations. ures of quality of life, global improvement or psychosocial factors? Is there a difference in efficacy between different drugs? Introduction 3.1.4 | Group 4 Question(s)—Comorbidities Improving daily performance, quality of life measures and increasing the ability to work are key aims of the management of nar- PICO 7 What is the clinical evidence of treatment for psychiatric comorbid symptoms? colepsy given their severe impact. Special condition: Driving The ability to drive safely and the adverse effects of EDS are Introduction often extremely important issues for patients and their families. Psychiatric disturbances are frequently present (20%–30%) in Driving regulations for people suffering from narcolepsy vary be- narcolepsy, particularly depression and anxiety, potentially as a sec- tween European countries although successful treatment often al- ondary phenomenon reflecting the psychosocial burden of the dis- lows patients to drive. However, any risk in driving crucially depends ease (Bassetti et al., 2019). Either near diagnosis or during the course on patients recognizing or monitoring their levels of EDS and refrain- of the illness, psychiatric symptoms may require management. ing from driving if appropriate. Recommendations Recommendations It is suggested that psychiatric disorders in narcolepsy should No specific recommendations were provided. Clinical global im- be treated in accordance with general principles for a general pop- pression, quality of life and prevention of everyday life risks were ulation. Shared compounds for the symptoms of narcolepsy and considered to substantiate the recommendations on symptomatic depression should be considered where appropriate such as anti- treatments. Single drugs in Table S8 report the synthesis of effect depressants for cataplexy and comorbid mood disorder (Weak rec- on these outcomes. ommendation). Depressive symptoms need regular re- evaluation Future directions/outlook (Barateau et al., 2020). In future trials, more attention should be given to quality of life The lack of specific studies does not provide support for any par- measures together with other patient reported outcome measures. ticular treatments for depression in narcolepsy. There is no reason, however, consider well-established treatments for major depression in the general population to be less effective in narcolepsy. Future directions/outlook 3.1.5 | Group 5 Question(s)—Symptomatic pharmacological treatment in children Specific non- pharmacological approaches including cognitive behavioral therapy and pharmacological approaches for psychiatric PICO 10 co-morbidities in narcolepsy are implicitly needed. What is the clinical evidence for efficacy of pharmacological treatment of any symptom of narcolepsy (including metabolic PICO 8 problems such as obesity and precocious puberty) in children? What is the clinical evidence of efficacy and safety for treatment of Is there a difference in efficacy between different treatments? other sleep disorders in narcolepsy such as RBD, sleep-disordered breathing, parasomnias, RLS/PLMS? Is there a difference in efficacy between different drugs or approaches? Introduction Initial symptoms of narcolepsy occur before the age of 18 in over 50% of patients (Bassetti et al., 2019) and may start at a very Introduction young age also before puberty onset (Postiglione et al., 2018). The A variety of sleep disorders such as RLS (prevalence 10%–20%), nature of narcoleptic symptoms in childhood and adolescence such sleep apnoea (20%–4 0%) or RBD (25%–70%) are more frequent in as cataplexy and EDS differs from the adult picture and may change narcolepsy than in the general population (Bassetti et al., 2019). The over time (Pizza et al., 2013). Treatment strategies including a non- underlying aetiology of other sleep disorders and their clinical im- pharmacological approach are different from adult strategies and pact on narcolepsy remain unclear although specific treatments are require taking into account the developmental aspects. Particular often warranted. attention is needed when evaluating safety and the risk-to-benefit Recommendations –Other sleep disorders in narcolepsy should be ratio of any treatment. Potential treatment side effects such as treated in accordance to the general recommendations for their specific mood disorder and metabolic upset leading to weight gain or loss treatment in non-narcoleptic patients. should be proactively assessed. 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 17 7 of 17 To date there are no established recommendations for the This part was completed applying an informal method of con- use of narcoleptic drugs when considering pubertal development. sensus, based on an extensive literature review, expert opinion and Endocrinologists who may prescribe adapted treatments in the case discussion. The task force reached consensus and agreed on the fol- of advanced puberty should carefully monitor pubertal development. lowing recommendations. Table S10 provides additional information on the medication. Recommendations See Figure 2 and Table S9. Future directions/outlook Compounds for the treatment of narcolepsy in children were 4.1 | Pathway for the management of narcolepsy approved only recently, following appropriate trials. The clinical efficacy of sodium oxybate for the treatment of EDS and cataplexy See Figures 3 and 4. in children was first reported in 2018. Trials on the safety and efficacy of pitolisant in children are yet to be published and will start soon for solriamfetol. More studies and approved treatments 4.1.1 | Overview of the impact on symptoms of frequently used drugs (adults) are needed for the management of children and adolescents with narcolepsy. See Figure 5. 3.1.6 | Overview of quality of evidence and recommendations 4.2 | Particular situations Experts discussed several particular situations in narcolepsy in the See Figures 1 and 2. absence of any published evidence from formal studies, leading to recommendations that are exclusively based upon expert knowl- 4 | PATH WAY, S TATE M E NT S A N D E X PE RT R ECO M M E N DATI O N S This guideline provides recommendations that are primarily edge and experience. The task force reached full consensus for these recommendations. 4.2.1 | Pregnancy breastfeeding, and contraception evidence-based together with opinions from experts. Several clinical questions cannot be satisfactorily addressed because of lim- In the majority of patients, the symptoms of NT1, particularly cata- ited evidence and lack of RCTs. Furthermore, firm conclusions are plexy, appear to become milder during pregnancy. However, there hampered by a limited systematic approach to formal assessment are no prospective studies and only few published retrospective of symptoms and outcomes using a variety of non-validated and vali- studies on this topic (Maurovich-Horvat et al., 2010; Thorpy et al., dated measures. Almost no head-to-head trials between drugs have 2013). Because of the teratogenic potential of all drugs used in the been performed. treatment of narcolepsy and other risks of complications during Drug 1 EDS Cataplexy QoE Rec QoE Modafinil ↑↑ ⊕⊕⊕⊖ ↓↓ ⊕⊕⊖⊖ no data Pitolisant ↑↑ ⊕⊕⊕⊖ ↑- ⊕⊕⊕⊖ no data ↑- ⊕⊕⊖⊖ Sodium Oxybate ↑↑ ⊕⊕⊕⊖ ↑↑ ⊕⊕⊕⊖ ⊕⊕⊕⊖ ↑- ⊕⊕⊖⊖ ↑↑* ⊕⊕⊕⊖ ↓↓ ⊕⊕⊕⊖ no data ↑↑ ⊕⊕⊖⊖ no data ↓↓ ⊕⊖⊖⊖ no data ↓↓ no data Antidepressants Amphetamine derivates ↑- ⊕⊕⊖⊖ Methylphenidate ↑- ⊕⊕⊖⊖ Zolpidem/Zopiclone Rec SP/HH Rec Solriamfetol 2 DNS ↑↑ ↓- # QoE Rec QoE no data ↑- Recommendations For Strong ↑↑ For Weak ↑- Against Weak ↓- no data Against Strong ↓↓ ⊕⊕⊖⊖ Quality of Evidence no data no data no data ⊕⊕⊖⊖ no data High ⊕⊕⊕⊕ Moderate ⊕⊕⊕⊖ Low ⊕⊕⊖⊖ Very Low ⊕⊖⊖⊖ Order: 1. EU-approved medications (in alphabetic order); 2. EU-frequently used medications for narcolepsy; * needs further evaluation from clinical practice; # chronic use not recommended F I G U R E 1 Overview of recommendations and of quality of evidence (adults) (SP, sleep paralysis; HH, hypnagogic/hypnopompic hallucinations) 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | BASSETTI et al. | BASSETTI et al. Drug EDS Rec Cataplexy QoE Rec QoE DNS Rec SP/HH QoE Rec QoE Recommendations Sodium Oxybate ↑↑ ⊕⊕⊖⊖ Methylphenidate ↑- ⊕⊖⊖⊖ Modafinil ↑- ⊕⊖⊖⊖ Pitolisant ↑-* ⊕⊖⊖⊖ ↑↑ ↓↓ ⊕⊕⊖⊖ ↑- no data ↑- no data For Weak ↑- no data no data Against Weak ↓- no data no data no data Against Strong ↓↓ ⊕⊖⊖⊖ ⊕⊖⊖⊖ no data Quality of Evidence ⊕⊖⊖⊖ no data no data Solriamfetol no data no data no data no data no data no data no data no data Amphetamine derivates ↑- ↑↑ no data Antidepressants ↑- For Strong ↑- ⊕⊖⊖⊖ High ⊕⊕⊕⊕ Moderate ⊕⊕⊕⊖ Low ⊕⊕⊖⊖ Very Low ⊕⊖⊖⊖ Order: EU-frequently used medications for narcolepsy (strong, weak recommendation, no recommendation). Only Sodium Oxybate EU- approved. All other medications are not approved for the use in children (off-label); * Very limited data, in particular on safety, further evaluation needed. F I G U R E 2 Overview of recommendations and of quality of evidence (children) (SP, sleep paralysis; HH, hypnagogic/hypnopompic hallucinations) Pharmacological management EDS unique/ main symptom Monotherapy (alphabecal order): 1st LINE ➤ MODAFINIL or ➤ PITOLISANT or ➤ SOLRIAMFETOL* Consider opmal dosage and traon If not or only parally effecve aer 4-6 weeks: change to another monotherapy, if not successfull, change to second line opons 2nd LINE Change to combinaon therapy: ➤ PIT and MOD or SOL ➤ SXB # and any WPA or Change to monotherapy: ➤SXB # or ➤MPH or ➤AMPH EDS and Cataplexy EDS, Cataplexy and DNS Monotherapy: Monotherapy: cataplexy) Combinaon therapies: ➤ SODIUM OXYBATE # or ➤ PITOLISANT (mild-moderate Combinaon therapies: ➤ VEN/CLO, and 1.line WPA or ➤ SXB # and 1.line WPA Consider opmal dosage and traon If not or only parally effecve aer 4-6 weeks: change to second line opons Change to combinaon therapy: ➤ Exchange SXB # to VEN/CLO (and vice versa) or ➤ SXB # , VEN/CLO and 1.line WPA or ➤Exchange VEN/CLO to another AD F I G U R E 3 Clinical pathway for the management of narcolepsy (adults) ➤ SODIUM OXYBATE # ➤ SXB # and/or VEN/CLO, and 1. line WPA or ➤ Any WPA, VEN/CLO and (only exceponally and only short-term) z-drugs DNS = Disturbed nocturnal sleep WPA = wake-promong agents (MOD, SOL, PIT, MPH, AMPH) MOD = Modafinil; SOL = Solriamfetol; PIT = Pitolisant; SXB = Sodium Oxybate; VEN = Venlafaxine; CLO = Clomipramine (lowdose); MPH = Methylphenidate; AMPH = Amphetamines; AD = Andepressant *Suggested from trials, few clinical experience; # Consider sleep apnea before starng with SXB 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 17 9 of 17 pregnancy, it is strongly advised to discontinue all drugs before any worsens, potentially due to age-related accrual of additional sleep planned pregnancy (Bassetti et al., 2019). This discontinuation will disorders. The available evidence on such issues is very limited. nearly always have an adverse effect on symptom control which can It is difficult to establish whether the disorder becomes milder be particularly challenging prior to successful conception. If total or if patients simply improve their coping mechanisms over the discontinuation of drug therapy is thought not practicable, it is ad- years. Potentially, there may be a less demanding lifestyle after vised to limit treatment to monotherapy. retirement with more planned naps, for example. If there are no Of the drugs generally used in narcolepsy, low doses of antide- significant or relevant comorbidities, pharmacological treatment pressants seem relatively safe. However, a recent publication has of narcolepsy is not age dependent. The potential risk of worsen- raised doubts on the previously assumed safety of modafinil, report- ing pre-e xisting cardiovascular disease in the elderly age group, ing a high prevalence of congenital defects (Damkier & Broe, 2020). particularly with stimulants, may influence treatment options, as There are some data indicating a positive effect of L-carnitine in a may the presence of hypertension (Jennum et al., 2013; Kovalská reduction of total nap time during the day. (Miyagawa et al., 2013). et al., 2016). In general, reduced levels of activity in old age, with or with- The use of medication during breast-feeding in narcolepsy is not out comorbidities, may affect the impact of EDS and significantly generally advised. If a patient has a young child, initiating or restarting sodium oxy- increase its burden. When EDS is adversely affected by inevitable bate should only be considered if there is a partner or family member behavioural changes associated with age, manipulation of currently who can reliably oversee the care of the child at night. available drug treatment is rarely successful. Another issue related to pregnancy is the potential pharmacokinetic interaction of prescribed medications with oral contraceptives. Most of the recommended drugs in the treatment of narcolepsy seem to have no 4.2.3 | Anaesthesia relevant interaction. An exception is modafinil, and there is debate about pitolisant. The European Medicines Agency advises dose adjustment There are very few data assessing perioperative risk in NT1 as re- and/or additional measures to prevent pregnancy when initiating modaf- cently concluded by an expert panel (Hershner et al., 2019). In gen- inil or pitolisant treatment in women using low dose oral contraceptives. eral, there are no indications to suggest that narcolepsy itself is an independent risk factor for surgery although, depending on the type of anaesthesia, existing comorbidities and medication use may be of 4.2.2 | Narcolepsy in the elderly concern. Also, sudden discontinuation of narcolepsy medication may cause problems but is not necessary for most surgical procedures. Clinical experience suggests an improvement of symptoms of nar- Some narcolepsy patients can have a longer recovery time to wake colepsy such as cataplexy and EDS with age. However, DNS often up from anaesthesia. Pharmacological management EDS unique/ main symptom Monotherapy: 1st LINE ➤ MODAFINIL or ➤ METHYLPHENIDATE or ➤ SODIUM OXYBATE # or ➤ AMPHETAMINE DERIVATES or ➤ PITOLISANT* Consider opmal dosage and traon If not or only parally effecve aer 4-6 weeks: change to another monotherapy EDS and Cataplexy Monotherapy: ➤ SODIUM OXYBATE # or Combinaon therapy ➤MOD or MPH, and SXB # Other combinaon therapies: ➤ MOD, MPH, and VEN or ➤ MOD, MPH, or PIT, and VEN (or CLO, or another AD) and SXB # EDS, Cataplexy and DNS Monotherapy: ➤ SODIUM OXYBATE # Combinaon therapy: ➤ SXB # and/or VEN/CLO, and 1. line WPA Consider opmal dosage and traon If not or only parally effecve aer 4-6 weeks: change to second line opons DNS = Disturbed nocturnal sleep; WPA = wake-promong agents (MOD, PIT, MPH, AMPH); MOD = Modafinil; SOL = Solriamfetol; PIT = Pitolisant; SXB = Sodium Oxybate; VEN = Venlafaxine; CLO = Clomipramine (low-dose); MPH = Methylphenidate; MPH = Amphetamines; AD = Andepressant; *Preliminary, needs further results from clinical trials and clinical experience; # consider sleep apnea before starng with SXB F I G U R E 4 Clinical pathway for the management of narcolepsy (children) 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | BASSETTI et al. | BASSETTI et al. after falls and restarting cataplexy treatment or avoiding precipitating drugs. 5 | PATI E NT S EC TI O N — O PI N I O N S TATE M E NT Leontien Sickenga, Madeleine Wallenius, Connie Landstedt and Marleny Macario Argueta Understanding patients’ views and needs is central to developing good clinical practice and patient-oriented guidelines. Narcolepsy F I G U R E 5 Overview of recommendations of key pharmacological treatments (adults) patients’ representatives identified key areas of interest and made the following recommendations and suggestions. 1. When enquiring about the various symptoms of narcolepsy, 4.2.4 | Patients refractory to treatment physicians should be aware that expressions used by patients may diverge from those used by the medical establishment With an increasing pharmacological arsenal, it is becoming and lead to potential inaccuracy. Loose terms such as fatigue increasingly rare that patients with narcolepsy are truly re- and tiredness used to describe EDS may cause confusion and fractory to therapy. However, there are large inter-individual prompt more detailed interrogation of those symptoms relating differences in treatment effect sizes and occurrence of side to excessive sleepiness. Physicians should formulate questions effects. If a patient exhibits no response whatsoever to a va- openly without leading the patient. For example, when enquiring riety of treatments, it is advisable to reconsider the diagnosis about cataplexy, a general question such as ‘how do you react and clarify precise drug dosing and compliance. Also, it should when you laugh?’ is appropriate. Further, they should be able to be verified that they have adjusted their lifestyle appropriately probe other aspects of narcolepsy outside the core symptoms of and are not attempting to use medication to compensate for any EDS and cataplexy that may necessitate a fuller understanding lack of adjustment. A variety of combination therapies are pos- of sleep-wake disorders and more specialized medical training. sible in narcolepsy although there is little published evidence to 2. There is an unmet need for specialized ancillary health workers guide precise choices. including nurses and psychologists working in sleep centres spe- It should be noted that complete symptom control in narcolepsy cializing in narcolepsy. A nurse, in particular, could focus more on is relatively rare and medication often serves simply to limit the bur- practical issues and help manage the daily life of patients as well den of symptoms such as EDS. In published studies, it is common as addressing practical concerns. for less than 50% of treated patients to be normalized on subjective measures of EDS (Epworth sleepiness scale < 11). 3. Measures of treatment success used in clinical trials, for example, should be reconsidered. Patient reported outcome measures should be incorporated in the individualized management of patients. 4.2.5 | Emergencies 4. Physicians and specialized nurses should address non- pharmacological treatments more fully. Discussion of strategies In the context of narcolepsy, emergencies are rare, usually relating such as regular naps, exercise, good sleeping habits and regular to medication- induced intoxication or acute withdrawal effects. schedules are likely to help and additional input from a psycholo- Regarding the former, the clinical presentation clearly depends on gist/therapist or dietician may be needed. Patients should also be the specific medication that has been overused. The latter typi- directed to patient organizations and be given advice about ben- cally occurs in NT1 when long-term treatment of cataplexy with efits and social support when appropriate. anti-depressant therapy is suddenly discontinued, causing status cataplecticus, characterized by long sequences of cataplectic attacks without full recovery between episodes (Poryazova et al., 2005). Very rarely, particularly in children, the phenomenon can 6 | CO M M E NT S O N R ECO M M E N DATI O N S A N D FU T U R E D I R EC TI O N S occur spontaneously in the absence of treatment changes. The anti- hypertensive drug prazosin is an alpha 1 adrenoreceptor antagonist Narcolepsy typically has a pleomorphic clinical presentation and which may also aggravate cataplexy and even induce status cata- produces a considerable variety of different symptoms with a varia- plecticus (Aldrich & Rogers, 1989). Managing status cataplecticus ble clinical course. Prospective and long-term clinical observational focuses on environmental adjustments to avoid potential injuries studies would help define the natural course of narcolepsy and its 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 10 of 17 11 of 17 variants, improving the development of disease-modifying drugs and such as pregnant women and the elderly. This also applies to non- allowing a better long-term evaluation of symptomatic medications. pharmacological approaches including special diets, regular exercise Although the last 20 years have seen well-designed studies ana- and scheduled naps, for example. lyzing effectiveness and safety of several symptomatic drugs in nar- Finally, preliminary clinical and pre-clinical data from studies in- colepsy, some methodological flaws make results difficult to transfer vestigating hypocretin receptor agonists appear promising and could to clinical practice or to compare results between studies. One issue potentially herald a new approach to treatment in narcolepsy. Other of concern is that RCTs have had short periods of follow-up, usually potential techniques to restore hypocretin levels such as stem cell re- limited to around 2 months. In some instances, the so-called ‘with- placement or gene therapy remain experimental. Following on from drawal design’ has been applied, exposing the study to a high risk recent studies that have expanded our knowledge of the immune of bias. Additionally, older drugs used in narcolepsy such as anti- basis of narcolepsy, more specific immunomodulatory treatments depressants and traditional psychostimulants have been poorly in- close to disease onset are likely to be fruitful in the development of vestigated before the era of controlled studies and evidence-based much needed disease-modifying therapy. medicine. Our recommendations for the management of narcolepsy refer to the best available evidence and expert experience. Nevertheless, 7 | A D D ITI O N A L I N FO R M ATI O N amongst patients there is considerable inter-individual variation in the efficacy and side effect profile of all commonly used medica- Table S10 given an overview of medication (titration schedule, tions. This necessitates a precise individual treatment plan for each mechanism of action, dosage, half-life, European Medicines Agency patient, contingent on their pattern of symptoms, disease severity approval, possible treatment combinations) for narcolepsy in adults. and comorbid conditions. This may lead to (co-)treatment with substances that have traditionally been used in the treatment of narcolepsy but have not been studied properly in trials. 8 | G U I D E LI N E U PDATE It is important to acknowledge that EDS, the usually dominant symptom in narcolepsy, has multifaceted expressions including im- The present guideline will be updated in 5 years. In the case of major paired attention, poor vigilance and cognitive impairment which changes in the evidence on the existing benefits and harms of in- may be more difficult to treat than unwanted daytime sleep. These cluded interventions or if new interventions become available, this important expressions may not be adequately assessed if the main update could be approached earlier. focus is on sleep. Associated problems such as fatigue may be even more refractory to treatment. See the suggested pharmacological AC K N OW L E D G E M E N T S management algorithm in Figures 3 and 4. The patient representatives Leontien Sickenga, Madeleine Further information is required on the current armamentarium Wallenius, Connie Landstedt and Marleny Macario Argueta are of effective drugs with more head-to-head comparison trials along thanked for their valuable feedback, suggestions, opinion state- with studies that use drug combinations and a sufficiently long pe- ment and the fruitful collaboration. Further, Joke Jaarsma (EFNA) riod of follow-up. There is also limited information on levels of com- is acknowledged for support, Maria Camerlingo (Agenzia sanitaria e pliance with current treatments. sociale regionale, Regione Emilia-Romagna, Italy) for assisting in the Narcolepsy- relevant outcome measures are generally poorly search strategy, Julia Junior (Germany) for design support with the correlated with measurements of treatment efficacy used in clin- figures, Romano Hönger (Bern, CH) and Annika Triller PhD (Witten, ical trials. For example, sleep latency is a common outcome mea- Germany) for support with organizational assistance and Dr Stine sure whereas performance measures on attention tasks requiring Knudsen-Heier (Norway) for her important feedback. prolonged vigilance may be more informative for activities of daily living. Furthermore, by focusing on individual symptoms, the overall C O N FL I C T O F I N T E R E S T S impact of therapeutic interventions on narcolepsy is not properly Claudio Bassetti organized teaching events and conferences that addressed. There is therefore a need for validated disease severity were supported by Jazz, UCB Pharma and Bioprojet. One of his IIT scales along with global measures of how the disease impacts on studies is supported by UCB Pharma and Jazz. He has also partici- quality of life that incorporate patient-reported outcomes. Patient pated in advisory boards of UCB, Bioprojet, Takeda, Idorsia and Jazz involvement in the development of these measures is recommended. Pharmaceuticals. Ulf Kallweit has participated in advisory boards The Narcolepsy Severity Scale is a recently described first attempt of AOP Orphan Pharmaceuticals, Bioprojet, Harmony Biosciences, to assess narcolepsy symptoms in one single scale (Dauvilliers et al., Jazz, Takeda and UCB. Giuseppe Plazzi has participated in advisory 2020). This may have utility in the quantification of narcoleptic board of UCB, Bioprojet, Idorsia and Jazz Pharmaceuticals. Michel symptoms when monitoring or optimizing management strategies. Lecendreux has received consultancy and lecture fees from UCB, There is a significant lack of clinical trials investigating the whole Jazz Pharma, Bioprojet and participated in clinical trials Flamel- spectrum of pharmacological treatments for narcolepsy in chil- Avadel, Bioprojet and Jazz Pharmaceutical. Poul Jennum reports dren and other groups potentially meriting special consideration advisory board fees from UCB and Jazz, Ramin Khatami advisory 13652869, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jsr.13387 by Cochrane Netherlands, Wiley Online Library on [17/10/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License | BASSETTI et al. | BASSETTI et al. board and lecture fees from UCB, Geert Mayer advisory boards for formal analysis (supporting); investigation (supporting); supervi- UCB Belgium, UCB Pharma Germany, Jazz Pharma UK; speakers sion (supporting); writing—review and editing (supporting). Joan bureau for UCB Germany and Belgium, Jazz Pharma UK. Markku Santamaria: Data curation (supporting); formal analysis (support- Partinen reports grants from Academy of Finland, Bioprojet, Jazz ing); investigation (supporting); writing—review and editing (sup- Pharmaceuticals, personal fees from UCB- Pharma, GSK, Takeda, porting). Karel Šonka: Data curation (supporting); formal analysis MSD, Orion and Umecrine, outside the submitted work. Paul (supporting); investigation (supporting); project administration (sup- Reading has received speaker and consultancy fees from UCB porting); writing—review and editing (supporting). Yves Dauvilliers: Pharma and Bioprojet. Karel Šonka has received consultancy and Conceptualization (supporting); data curation (supporting); formal lecture fees from UCB and Sanofi and participated in clinical trials for analysis (supporting); investigation (supporting); methodology (sup- Flamel-Avadel, Jazz and Luitpold Pharmaceutical. Yves Dauvilliers porting); project administration (supporting); validation (support- has participated in advisory boards of UCB, Bioprojet, Theranexus, ing); writing—original draft (supporting); writing—review and editing Takeda, Avadel, Idorsia and Jazz Pharmaceuticals. Gert Jan Lammers (equal). Gert Jan Lammers: Conceptualization (supporting); data has participated in advisory boards of UCB, Bioprojet and Jazz curation (supporting); investigation (supporting); supervision (sup- Pharmaceuticals; one of his studies is supported by Bioprojet and he porting); validation (equal); writing—original draft (equal); writing— served as consultant for Jazz. Leja Dolenc-Groselj, Joan Santamaria, review and editing (equal). Luca Vignatelli, Elisa Baldin, Mauro Manconi and Thomas Pollmächer described no conflicts of interest. DATA AVA I L A B I L I T Y S TAT E M E N T The data that support the findings of this study are available in the AU T H O R C O N T R I B U T I O N S Supporting Information. Claudio L Bassetti: Conceptualization (equal); methodology (supporting); project administration (lead); supervision (equal); writing— ORCID original draft (equal); writing—review and editing (equal). Ulf Claudio L. A. Bassetti Kallweit: Conceptualization (equal); investigation (equal); methodol- Ulf Kallweit https://orcid.org/0000-0002-4535-0245 https://orcid.org/0000-0003-1975-6919 https://orcid.org/0000-0002-9051-7091 ogy (supporting); project administration (equal); supervision (equal); Luca Vignatelli writing—original draft (equal); writing—review and editing (equal). Giuseppe Plazzi Luca Vignatelli: Conceptualization (supporting); formal analysis Michel Lecendreux (lead); methodology (lead); project administration (supporting); su- Elisa Baldin https://orcid.org/0000-0002-1051-0472 https://orcid.org/0000-0003-4409-2931 https://orcid.org/0000-0002-3277-5623 https://orcid.org/0000-0002-8350-951X pervision (supporting); writing—original draft (supporting); writing— Leja Dolenc-Groselj review and editing (supporting). Giuseppe Plazzi: Conceptualization Ramin Khatami https://orcid.org/0000-0002-1092-6160 (supporting); formal analysis (supporting); investigation (support- Mauro Manconi https://orcid.org/0000-0002-1849-7196 ing); validation (supporting); writing—review and editing (sup- Markku Partinen https://orcid.org/0000-0002-8182-9368 porting). Michel Lecendreux: Data cur

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