VIEWS & REVIEWS OPEN ACCESS Stridor in multiple system atrophy Consensus statement on diagnosis, prognosis, and treatment Pietro Cortelli, MD, PhD,* Giovanna Calandra-Buonaura, MD, PhD,* Eduardo E. Benarroch, MD, Correspondence Giulia Giannini, MD, Alex Iranzo, MD, Phillip A. Low, MD, Paolo Martinelli, MD, Federica Provini, MD, PhD, Prof. Cortelli Niall Quinn, MD, Eduardo Tolosa, MD, PhD, Gregor K. Wenning, MD, PhD, Giovanni Abbruzzese, MD, pietro.cortelli@unibo.it Pamela Bower, Enrico Alfonsi, MD, Imad Ghorayeb, MD, PhD, Tetsutaro Ozawa, MD, PhD, Claudio Pacchetti, MD, Nicolò Gabriele Pozzi, MD, Claudio Vicini, MD, Angelo Antonini, MD, PhD, Kailash P. Bhatia, MD, Jacopo Bonavita, MD, Horacio Kaufmann, MD, Maria Teresa Pellecchia, MD, PhD, Nicole Pizzorni, MSc, Antonio Schindler, MD, François Tison, MD, PhD, Luca Vignatelli, MD, PhD, and Wassilios G. Meissner, MD, PhD ® Neurology 2019;93:630-639. doi:10.1212/WNL.0000000000008208 Abstract Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly in- spiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic con- ditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symp- tomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified. *These authors contribute equally to the manuscript. From the IRCCS (P.C., G.C.-B., G.G., F.P., L.V.), Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie (P.C., G.C.-B., G.G., P.M., F.P.), Università di Bologna, Bologna, Italy; Department of Neurology (E.E.B., P.A.L.), Mayo Clinic, Rochester, MN; Multidisciplinary Sleep Unit (A.I.), Neurology Service, Hospital Clinic de Barcelona, IDIBAPS CIBERNED, Barcelona, Spain; UCL Queen Square Institute of Neurology (N.Q.), Queen Square, London; Parkinson’s Disease and Movement Disorders Unit (E.T.), Neurology Service, Hospital Clinic de Barcelona; Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) (E.T.), University of Barcelona (UB), and Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain; Department of Neurology (G.K.W.), Innsbruck Medical University, Innsbruck, Austria; Department of Neuroscience (G.A.), Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy; The Multiple System Atrophy Coalition, Inc. (P.B.), Charlotte, NC; Neurophysiopathology Unit (E.A.), IRCCS “C. Mondino” Foundation, Pavia, Italy; Department of Clinical Neurophysiology (I.G.), CHU de Bordeaux, Bordeaux, France; Université de Bordeaux (I.G.), Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Bordeaux, France; CNRS (I.G.), Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Bordeaux, France; Department of Neurology (T.O.), Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minami Uonuma, Niigata, Japan; Parkinson’s Disease and Movement Disorders Unit (C.P., N.G.P.), IRCCS “C. Mondino” Foundation, Pavia; Dipartimento di Medicina Specialistica (C.V.), Diagnostica e Sper- imentale (DIMES), University of Bologna, Bologna, Italy; Dipartimento di Scienze biomediche e chirurgico specialistiche (C.V.), University of Ferrara, Ferrara, Italy; Department of Neurosciences (A.A.), University of Padua, Padua, Italy; Department of Clinical and Motor Neuroscience (A.P.B.), UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London; Spinal Unit (J.B.), Montecatone Rehabilitation Institute, Imola, Italy; Department of Neurology (H.K.), New York University School of Medicine, New York, NY; Department of Medicine (M.T.P.), Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy; “Luigi Sacco” Department of Biomedical and Clinical Sciences (N.P., A.S.), University of Milan, Milan, Italy; Service de Neurologie (F.T., W.G.M.), CRMR Atrophie Multisystématisée, CHU Bordeaux, Bordeaux, France; Univ. de Bordeaux (F.T., W.G.M.), Institut des Maladies Neurodégénératives, Bordeaux, France; and Department Medicine (W.G.M.), University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by IRCCS Istituto delle Scienze Neurologiche di Bologna. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 630 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Glossary CPAP = continuous positive airway pressure; DISE = drug-induced sleep endoscopy; IRCCS-ISNB = Istituto di Ricovero e Cura a Carattere Scientifico delle Scienze Neurologiche di Bologna; MSA = multiple system atrophy; MSA-C = MSA-cerebellar; MSA-P = MSA-parkinsonian; VPSG = video polysomnography. Multiple system atrophy (MSA) is a progressive neurodegen- from the Methodological Handbook of the Italian National erative disorder characterized by a variable combination of Guideline System.16 The consensus conference method is autonomic failure, cerebellar ataxia, and parkinsonian features, recommended for addressing important clinical questions typically poorly responsive to levodopa. The diagnostic criteria in the face of limited good quality evidence. The main define 3 degrees of certainty for diagnosis, possible, probable, outcome, a consensus statement, represents the collective and definite, and 2 phenotypes, parkinsonian (MSA-P) and opinions of an expert panel, derived from systematic re- cerebellar (MSA-C), according to the predominant feature at view and discussion of available evidence.17 The organizer the time of evaluation.1,2 Causes of death in MSA commonly of the Bologna Consensus Conference was the IRCCS- include bronchopneumonia, urosepsis, or sudden death that ISNB, Italy. Planning and execution of the project was often occurs during sleep.2 performed in 4 phases: (1) assignment, (2) scoping, (3) assessment, and (4) the consensus conference itself. All Several sleep-related breathing disorders, including stridor and activities, from conception to realization, were completed central and obstructive sleep apneas, frequently occur in between February and October 2017. During the same MSA.3,4 Stridor has been included in the diagnostic criteria as period, a parallel project on dysphagia in patients with additional feature for the diagnosis of possible MSA, showing MSA was performed. a high diagnostic positive predictive value.5–7 A recent study has suggested that early stridor onset is an independent risk factor In (1) the assignment phase, the entities and their roles were for shorter survival8; however, its prognostic role remains defined, and participants were nominated and invited. Four controversial.9–11 This may be a consequence of the distinct entities were appointed: (1) the Scientific Committee (6 design, population characteristics, and MSA diagnostic cer- members) planned and organized the whole project, nomi- tainty (clinical vs autopsy based) across studies. Furthermore, nated the Consensus Development Panel and Workgroup the lack of a universal definition for stridor and a gold standard members, and chose the questions to be answered by the for its diagnostic assessment may explain result heterogeneity. Workgroup; (2) the Technical Committee (2 members) established methods and rules of the Consensus Conference, Two main options have been suggested for treating stridor: assisted with defining questions, and performed the sys- tracheostomy or continuous positive airway pressure (CPAP).5 tematic review with evidence mapping; (3) 1 Workgroup of Tracheostomy is currently preferred in the advanced disease experts (8 members) focused on stridor, synthesized and stage for severe stridor and in case of stridor during wakefulness integrated information from the systematic review before the with immobile vocal cords on laryngoscopy.5 CPAP as a non- consensus conference, provided shared answers to the pro- invasive therapy can be used for mild and moderate intensity posed questions, and presented their findings during the stridor occurring during sleep and related obstructive apneas. Consensus Conference, including research gaps and a pro- However, guidelines for stridor management are lacking, and only a few studies have assessed the role of stridor treatment on posal for future research; and (4) the Consensus De- survival.8,12–14 The “Istituto di Ricovero e Cura a Carattere velopment Panel (8 members) chaired the Consensus Scientifico delle Scienze Neurologiche di Bologna” (IRCCS- Conference, established presentation procedures, and pro- ISNB) promoted an international consensus conference among vided final statements. experts in the field with methodological support, convened in Bologna, Italy, on October 6 and 7, 2017. The aims of the In (2) the scoping phase, the scope and the protocol for the conference were to (1) determine criteria for the diagnosis of systematic review (registered on PROSPERO database, stridor and consequently define stridor in MSA, (2) define the PROSPERO 2018 CRD42018079084)18 and the protocol prognostic value of stridor on MSA survival, (3) suggest ther- for the conference were defined. The Scientific Committee apeutic options for stridor, and (4) provide statements for future identified the topics and together with the Technical research after systematically reviewing evidence and identifying Committee formulated the questions to be addressed. The unmet needs for clinical practice and research gray zones. questions were framed according to the Problem/Patient/ Population, Intervention/Indicator, Comparison, Out- come model.19 Methods In (3) the assessment phase, the Technical Committee per- The method was inspired by the US National Institutes of formed a systematic review with evidence mapping to assess the Health Consensus Development Program15 and adapted state of knowledge on stridor in MSA. The systematic review Neurology.org/N Neurology | Volume 93, Number 14 | October 1, 2019 631 was performed following accepted criteria for the good conduct included the consensus conference participants and other and reporting of systematic reviews18 and reported according to members of the scientific community and officials from the Preferred Reporting Items for Systematic Reviews and Meta- organizing institution. Finally, experts gave a presentation on Analyses guidelines.20 The descriptive map of available research needs for future research. evidence was performed by adapting the methodology reported by the Global Evidence Mapping Initiative,21 which involved detailed coding of included studies and in-depth syntheses of Results the available research. Studies eligible for inclusion were pub- Systematic review with evidence mapping lished studies of any kind of design reporting original data on The literature search was performed in July 2017 and retrieved subjects with MSA having stridor during sleep, dealing with 212 citations after duplicate removal (figure). Each retrieved diagnosis, prognosis, and/or treatment. Studies published in article was screened to assess potential relevance, and 53 were abstract form, narrative review, or concept papers were ex- reviewed from the full text for inclusion. A total of 42 studies cluded. Published studies were identified from the National finally met the prespecified inclusion criteria, and 34 were used Library of Medicine’s MEDLINE database, Elsevier’s EMBASE as basis for the statements. The majority of studies on diagnosis database, and the Cochrane Central Register of Controlled and treatment were of Class IV quality; those on prognosis of Trials by means of specific search strategies, using a combina- Class III (tables 1–4). Most studies on diagnosis and treatment tion of exploded MeSH terms and free text combing the con- included fewer than 10 patients and were case series or case cepts of stridor in sleep and MSA (see protocol on PROSPERO reports as design. The cohort design was used in the majority of for details). Reference lists of identified articles were reviewed to prognosis studies. find additional references. All abstracts or full articles without electronic abstracts were reviewed independently by 2 reviewers Diagnosis of stridor to identify potentially relevant studies. Each study was classified Stridor is a respiratory disturbance that in MSA typically occurs according to various descriptors, including topic domain, sam- during sleep and might develop at any time point in the disease ple size, design, presence of diagnostic criteria of the stridor, and process. According to clinical and clinicopathologic studies, level of evidence according to the Classification of Evidence stridor prevalence in MSA ranges from 12% to 42%8–12,23–25 and Schemes of the Clinical Practice Guideline Process Manual of is similar in MSA-C and MSA-P.8,9,11,12 In 2 studies, 4%–5.2% of the American Academy of Neurology (2011).22 Briefly, each patients presented stridor as an initial manifestation of MSA.8,26 study was graded according to its risk of bias from Class I (highest quality) to Class IV (lowest quality). Risk of bias was The clinical diagnosis of stridor remains challenging. The judged by assessing specific quality elements (i.e., study design, presence of a nighttime witness is typically necessary to suspect patient spectrum, data collection, and masking) for each clinical stridor because patients may be unaware of it. A high-pitched topic (diagnostic accuracy, prognostic accuracy, and therapeu- sound or heavy snoring are the symptoms frequently reported tic). Disagreement between the 2 reviewers was resolved by in patients who eventually turn out to have stridor, illustrating discussion. the problem of the differential diagnosis with snoring and ob- structive sleep apnea syndrome, which are 2 other frequent The Technical Committee then sent to the Workgroup sleep-related breathing disorders in MSA.3,4,10,24,27–29 experts a detailed summary of the systematic review with evidence mapping, the questions, and the abstracts of the The term “peculiar snoring” was initially used to describe the most prominent studies, classified by topic and quality. The distinctive noise occurring in MSA due to vibration of the vocal workgroup produced draft answers to be discussed during the folds in inspiration, with a fundamental acoustic frequency of Consensus Conference. 260–330 Hz, different from that of ordinary soft palate snor- ing.30 Subsequently, only a single study has analyzed the The Consensus Conference (4) was held over 2 days (Oc- acoustic features of stridor in 22 patients with MSA by means of tober 6 and 7, 2017) in Bologna. On the first day, the Con- the Multi-Dimensional Voice Program.31 This study showed sensus Development Panel established the rules for the open that stridor can be decomposed into rhythmic and semi- discussion meetings, appraised the state of knowledge on rhythmic waveforms. In both cases, it comprises formats and stridor in MSA and the preliminary answers provided by harmonics, whose presence suggests an origin in the vocal experts, and proposed future strategies for the publication of cords. In contrast, the sound analysis of snoring that was the consensus statements. During a contemporaneous closed available for 18 of these patients revealed an irregular-shaped meeting, the experts independently discussed and reached sound with no formats and harmonics. final answers to the questions assigned to them. Finally, an open discussion was held in which experts presented their Studies with video polysomnography (VPSG), which include findings and all participants debated openly to reach con- audio recording and concurrent evaluation of vocal cord sensus regarding each topic and the need for further research. motion by fiberoptic laryngoscopy, showed that the high- On the second day, the Consensus Development Panel pitched sound identified as stridor in patients with MSA was drafted a summary of the findings in a closed session. The associated with impaired vocal cord abduction, paradoxical chairperson then reported the findings in an open session that adduction, or both during inspiration and expiration, leading 632 Neurology | Volume 93, Number 14 | October 1, 2019 Neurology.org/N Figure Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram Process and result of the systematic search for studies on stridor in multiple system atrophy. to narrowing of the rima glottidis. This indicates that in- cord abduction of varying severity or normal vocal cord spiratory vibration of the narrowed vocal cord folds causes motility.27,29,32,33,35,36,39–44 Conversely, impairment of vocal stridor.32–38 cord motility during wakefulness was also observed in patients with MSA without stridor during sleep.27 In 1 VPSG study exploring breathing activity and EMG ac- tivity of the respiratory muscles, stridor was accompanied by Studies with drug-induced sleep endoscopy (DISE) dem- overactivation of intercostalis and diaphragmatic muscles. In onstrated impaired abduction or paradoxical adduction this study, the observation of tonic and subcontinuous muscle of the vocal cords in patients with MSA with stridor recruitment with phasing out of thoracic as opposed to ab- who had normal vocal cord motility on awake dominal respiratory traces with paradoxical inward move- laryngoscopy.32,33,35–37,41–44 ments of the abdominal wall during inspiration was suggestive of paradoxical breathing.37 Finally, a few studies have performed EMG of laryngeal muscles during wakefulness and drug-induced sleep. Further VPSG studies showed that other sleep-related re- Patients with MSA with stridor could present normal EMG spiratory disturbances such as snoring, central and obstructive activity of adductor and abductor laryngeal muscles during sleep apneas, and breathing rate abnormalities (i.e., a patho- quiet breathing and inspiration. Alternatively, they could logic breathing rate increase during non-REM and sleep) may occur in patients with MSA with and without show a neurogenic pattern of muscle unit action potential stridor.12,24,33,37–39 analysis of these muscles associated with tonic activity of adductor muscles during quiet breathing and paradoxical Laryngoscopy during wakefulness in patients with MSA with activity during inspiration. During drug-induced sleep, the stridor, performed to exclude secondary causes or functional main patterns were persistent tonic activity or paradoxical vocal cord abnormalities related to other neurologic con- activation of laryngeal adductor muscles during ditions, can reveal bilateral or unilateral impairment of vocal inspiration.35–38,44–46 Neurology.org/N Neurology | Volume 93, Number 14 | October 1, 2019 633 Table 1 Descriptive features of eligible studies on stridor in MSA All No. of patients = number Cohort Case-control Cross-sectional Case Case Evidence studies of studies studies studies studies series report class Topic N N N N N N N Diagnosis 24 <10 pts = 14 studies — 2 5 10 7 All studies Class IV 10–19 pts = 7 studies 20–50 pts = 3 studies Prognosis 11 <50 pts = 6 studies 10 — — 1 — 2 Class II 50–99 pts = 3 studies 8 Class III >100 pts = 2 studies 1 Class IV Treatment 25 <10 pts = 12 studies 8 — — 10 7 3 Class III 10–19 pts = 6 studies 22 Class IV 20–50 pts = 7 studies Abbreviation: MSA = multiple system atrophy; pts = patients. Each study is graded according to its risk of bias from Class I to Class IV (with I being highest and IV lowest quality). Statements on the diagnosis of stridor Laryngoscopy for assessing stridor Clinical features suggesting the presence of stridor Statements are based on core literature consisting of Class Statements are based on core literature consisting of Class IV IV level studies27,29,32–37,39–44 and expert opinion. level studies10,12,24,31 and expert opinion. c Laryngoscopy can exclude mechanical lesions (e.g., c Stridor is suspected when a high-pitched breathing sound masses and scars) or functional vocal cord abnormalities is emitted by the patient during sleep or while awake, or related to different neurologic conditions (central or when reported by caregivers. peripheral disorders). c Stridor is probably underrecognized because patients and c Laryngoscopy may reveal vocal cord motility impairment caregivers may be unaware of its presence, especially in patients with MSA with stridor. when it occurs at night. c If awake laryngoscopy is normal, DISE might be considered c Recognition could be possible by the patient or if the suspicion of sleep-related stridor needs confirmation. caregiver after imitation of stridor by the physician (see supplementary sound track file, links.lww.com/ Other investigations for assessing stridor WNL/A973). Statements are based on core literature consisting of Class IV level studies35–38,44–46 and expert opinion. Home audio recording to support the diagnosis of stridor Statement is based on expert opinion because literature on the c There is no evidence that other investigations are useful. use of home audio recording to support the diagnosis of c EMG of the laryngeal muscles may show denervation or stridor (differential diagnosis of stridor from snoring) is abnormal hyperactivity. lacking. Conclusion on diagnostic criteria for stridor and definition of stridor in MSA c Patients and caregivers should be encouraged to audio c Stridor in MSA is a strained, high-pitched, harsh record episodes of suspected stridor. respiratory sound, mainly inspiratory, caused by laryngeal dysfunction leading to narrowing of the rima glottidis. It VPSG to support the diagnosis of stridor may occur only during sleep or it may be present both Statements are based on core literature consisting of Class IV during sleep and wakefulness. level studies10,12,24,31,33,37–39 and expert opinion. c Stridor may be recognized clinically if present at the time of neurologic examination, with the help of a witness, or c VPSG including audio is not necessary if the physician by listening to an audio recording. has already diagnosed stridor. c Laryngoscopy is suggested to exclude mechanical lesions c VPSG including audio may demonstrate stridor and its (e.g., masses and scars) or functional vocal cord inspiratory nature. abnormalities related to different neurologic conditions c VPSG can characterize other sleep sounds. (central or peripheral disorders). 634 Neurology | Volume 93, Number 14 | October 1, 2019 Neurology.org/N Table 2 Studies that form the basis of the statements on diagnosis with their level of evidence Level of First Diagnostic evidence author, y Design No. of patients Diagnostic test criteria of stridor class Alfonsi, Cross- 17 (11 with stridor) + 40 EMG; polysomnography No IV 2016 sectional normal controls Blumin, Case 7 Fiberoptic laryngoscopy No IV 2002 series Chitose, Case 1 Awake and sleep-induced laryngoscopy No IV 2012 report Hanson, Cross- 12 (9 with stridor) + Speech analysis No IV 1983 sectional controls Harcourt, Case 18 Endoscopy; polysomnography No IV 1996 series Iranzo, 2004 Cross- 40 (14 with stridor) Polysomnography No IV sectional Isono, 2001 Case 10 EMG under anesthesia and sleep No IV series Isozaki, Case- 7 Awake and sleep-induced laryngoscopy No IV 1996 control Koo, 2016 Cross- 22 Acoustic analysis Yes IV sectional Merlo, 2002 Case 7 EMG pattern No IV series Nonaka, Case 5 Sleep-induced laryngoscopy; EMG No IV 2006 series Sadaoka, Case- 8 Polysomnography; esophageal pressure manometry/ Yes IV 1996 control endoscopy Sadaoka, Case 8 Acoustic analysis of snoring, polysomnography, No IV 1997 series fiberscopic examination under sedation Shiba, 2006 Case 1 EMG No IV report Shimohata, Case 1 Polysomnography No IV 2006 report Shimonata, Case 21 (5 with stridor) Polysomnography, laryngoscopy during wakefulness No IV 2007 series and under anesthesia Silber, 2000 Cross- 42 (17 with stridor) Polysomnography Yes IV sectional Stomeo, Case 1 Sleep-induced endoscopy/sound analysis No IV 2016 report Vetrugno, Cross- 19 (8 with stridor) Polysomnography; intraesophageal pressure Yes IV 2004 sectional recording in 3 patients Vetrugno, Case 3 Polysomnography including intraesophageal pressure No IV 2007 series recording; laryngoscopy; EMG Williams, Case 12 Fiberoptic laryngoscopy No IV 1979 series Each study was classified according to various descriptors, including topic domain, sample size, design, presence of diagnostic criteria of the syndrome, and level of evidence according to the Classification of Evidence Schemes of the Clinical Practice Guideline Process Manual of the American Academy of Neurology (2011). Each study was graded according to its risk of bias from Class I to Class IV (with I highest quality and IV lowest quality). Risk of bias was judged by assessing specific quality elements (i.e., study design, patient spectrum, data collection, and masking) for each clinical topic (diagnostic accuracy, prognostic accuracy, and treatment). c If awake laryngoscopy is normal and the suspicion of and (2) VPSG to document the inspiratory nature of the sleep-related stridor needs confirmation, the following sound, the presence of expiratory intercostalis activation, additional evaluations might be considered: (1) DISE or the presence of associated sleep breathing disorders. Neurology.org/N Neurology | Volume 93, Number 14 | October 1, 2019 635 Table 3 Studies that form the basis of the statements on prognosis with their level of evidence First author, y Design No. of patients Level of evidence Coon, 2015 Cohort 685 (176 with stridor) II Giannini, 2016 Cohort 136 (42 with stridor) III Glasmacher, 2017 Systematic review 6 studies Not available Koo, 2016 Cohort 22 III Krim, 2007 Cohort 86 (17 with stridor) II Lalich, 2014 Cohort 38 (25 with stridor) III Silber, 2000 Cohort 42 (30 with follow-up data, 11 with stridor) III Starhof, 2016 Cohort 99 (44 with stridor) II Tada, 2007 Cohort 49 (18 with stridor) III Yamaguchi, 2003 Cohort 83 (33 with stridor) III Each study was classified according to various descriptors, including topic domain, sample size, design, presence of diagnostic criteria of the syndrome, and level of evidence according to the Classification of Evidence Schemes of the Clinical Practice Guideline Process Manual of the American Academy of Neurology (2011). Each study was graded according to its risk of bias from Class I to Class IV (with I highest quality and IV lowest quality). Risk of bias was judged by assessing specific quality elements (i.e., study design, patient spectrum, data collection, and masking) for each clinical topic (diagnostic accuracy, prognostic accuracy, and treatment). Prognostic value of stridor c Stridor can be distressing for patients and caregivers. Retrospective cohort studies have reported conflicting results c The impact on health-related quality of life remains to be on the prognostic value of stridor.47 Seven studies did not find determined. an association between the presence of stridor during the disease course and shortened survival.8,9,11,14,48–50 In most of Treatment of stridor these studies, stridor was clinically suspected without in- Four retrospective studies reported that the treatment of strumental confirmation. In contrast, 1 study showed shorter stridor improves survival.8,12–14 Stridor treatment mainly survival in patients with MSA with stridor after VPSG re- comprised CPAP or tracheostomy.10,27,29,32,33,35,39,51,52 In 3 cording, but not from disease onset.10 Finally, the largest studies (<15 patients), CPAP initially eliminated stridor in study with VPSG found that early onset of stridor (within 3 almost all patients,12,13,51 but the long-term symptomatic ef- years from motor or autonomic symptom onset) was an in- fect remains unknown. dependent predictor of shorter survival.8 Based on an analysis with the Multi-Dimensional Voice Program, 1 study reported Three studies reported survival in patients with MSA treated that acoustic features of stridor may affect survival in MSA.31 with CPAP. In 1 small study, CPAP had no effect on sur- vival.10 In another prospective cohort study, patients with Statements on the prognostic value of stridor MSA with stridor receiving CPAP (n = 13) had similar me- Effect of stridor on survival dian survival compared with a group of patients with MSA Statements regarding the effect of stridor on survival in MSA without stridor (n = 26).12 Sudden death was reported in 2 of are based on core literature consisting of Class II/III level 13 patients following CPAP initiation.13 studies,8–11,14,31,48–50 a systematic review,47 and expert opinion. Classic tracheostomy is usually the surgical procedure of c Whether stridor affects survival is uncertain. choice for stridor. This involves the positioning of a fenes- c Stridor within 3 years of motor or autonomic symptom trated cannula, maintained closed during the day to allow onset may shorten survival. However, identification of phonation.53 Alternative techniques such as skin-lined tra- stridor onset may be difficult. cheostomy have recently been proposed for the treatment of c Whether specific features of stridor affect survival remains severe stridor in MSA.54 Skin-lined tracheostomy offers sev- to be determined. eral advantages, such as a greater opening of the stoma, higher c Stridor during wakefulness is widely considered to reflect stability over time, less risk of granulation tissue, and re- a more advanced stage of the disease than stridor versibility. In addition, it does not require a cannula during the occurring during sleep. night, and the stoma is easy to plug during the day. Effect of stridor on well-being or health-related quality of life Three studies focused on the role of tracheostomy on survival. Literature on the effect of stridor on well-being or health-related In the largest retrospective study (n = 42 with stridor), quality of life is lacking. Statements are based on expert opinion. patients treated with tracheostomy had longer overall disease 636 Neurology | Volume 93, Number 14 | October 1, 2019 Neurology.org/N Table 4 Studies that form the basis of the statements on therapy with their level of evidence First author, y Design No. of patients Treatment Level of evidence Blumin, 2002 Case series 7 CPAP: bilevel positive airway pressure; tracheostomy IV Chitose, 2012 Case report 1 CPAP; laser arytenoidectomy IV Ghorayeb, 2005 Case series 22 (15 with stridor) CPAP IV Giannini, 2016 Cohort 136 (42 with stridor; 31 treated) CPAP (19 pts); tracheostomy (12 pts) III Harcourt, 1996 Case series 18 CPAP (2 pts); tracheostomy (2 pts); arytenoidectomy (3 pts) IV Iranzo, 2000 Cohort 20 (5 with stridor) CPAP IV Iranzo, 2004 Cohort 14 (with stridor) CPAP (13 pts) IV Isono, 2001 Case series 10 CPAP on laryngeal resistance and muscle activity (6 pts) IV Isozaki, 1996 Case series 7 Tracheostomy IV Jin, 2007 Case series 18 Tracheostomy (7 pts) IV Kneisley, 1990 Case report 1 Arytenopexy; vocal cord pinning IV Lalich, 2014 Cohort 1 CPAP IV Mahmud, 2015 Case report 1 Laser arytenoidectomy and posterior cordotomy IV Merlo, 2002 Case series 7 Botulinum toxin (4 pts) IV Sadaoka, 1996 Case series 8 Tracheostomy IV Silber, 2000 Cohort 42 (30 with follow-up data) CPAP (5 pts); tracheostomy (4 pts) IV Stomeo, 2016 Case report 1 Subtotal arytenoidectomy IV Tada, 2007 Cohort 18 (with stridor) Tracheotomy (12 pts) III Williams, 1979 Case series 12 Tracheostomy (4 pts) IV Yamaguchi, 2003 Cohort 33 (with stridor; 15 treated) CPAP; tracheostomy; laryngectomy III Abbreviation: CPAP = continuous positive airway pressure; pts = patients. Each study was classified according to various descriptors, including topic domain, sample size, design, presence of diagnostic criteria of the syndrome, and level of evidence according to the Classification of Evidence Schemes of the Clinical Practice Guideline Process Manual of the American Academy of Neurology (2011). Each study was graded according to its risk of bias from Class I to Class IV (with I highest quality and IV lowest quality). Risk of bias was judged by assessing specific quality elements (i.e., study design, patient spectrum, data collection, and masking) for each clinical topic (diagnostic accuracy, prognostic accuracy, and treatment). duration, longer disease duration after stridor onset, and c Consider ventilation during sleep (CPAP) as a first-line longer disease duration after treatment compared with those symptomatic therapy. treated with CPAP.8 Another study showed that tracheos- c Tracheostomy bypasses upper airway obstruction at tomy may reduce the risk of death and of sudden death in laryngeal level and relieves distressing stridor. Tracheos- patients with MSA with stridor.11 One study reported that 2 tomy is effective in the symptomatic control of stridor. of the 4 patients with tracheostomy died 1 year after the c Persistent and severe stridor may require tracheostomy. sleep evaluation, whereas the other 2 were alive 1.9 and 7 years later.10 CPAP for improving survival of patients with stridor Statement is based on core literature consisting of Class III/IV Single case reports have described the use of posterior cordotomy level studies.8,10,12,13 and arytenoidectomy,28,43,44,55 and botulinum toxin relieved dystonic stridor in 3 of 4 patients 1 month after inoculation.45 c Whether CPAP improves survival in patients with MSA with stridor is uncertain. Statements on the treatment of stridor Treatment for symptomatic control of stridor Tracheostomy for improving survival of patients with stridor Statements are based on core literature consisting of Class III/ Statement is based on core literature consisting of Class III/IV IV level studies8,10–14,27,29,32,33,35,39,49,51,52 and expert opinion. level studies.8,10,11 c Ventilation during sleep (CPAP) can be useful in the c Tracheostomy might improve survival in patients with symptomatic control of stridor. stridor. Neurology.org/N Neurology | Volume 93, Number 14 | October 1, 2019 637 Other treatment options for stridor determined. Finally, the usefulness of bilevel PAP should be Statement is based on core literature consisting of Class IV compared with CPAP. Similarly to CPAP, interventional studies level studies including case reports.28,43–45,55 should also compare skin-lined vs conventional tracheostomy. c There is insufficient evidence for minimally invasive Literature revision and the emergence of several research gaps procedures and botulinum toxin injections for the on diagnosis, prognosis, and treatment for stridor rise the symptomatic treatment of stridor. need of prospective multicenter studies on large samples, and with a randomized controlled design concerning its treat- ment, to provide high level of evidence in the role of stridor in Research needs MSA course. The present Consensus Conference represents the first effort to systematically revise the literature and to provide state- Author contributions ments on stridor, a specific feature of MSA, that could affect Scientific Committee: P. Cortelli (Chair), G. Calandra- the disease course. However, despite the importance of this Buonaura, F. Provini, P. Martinelli, A. Iranzo, and P. A. Low. topic, the majority of studies available in the literature were of Technical Committee: L. Vignatelli and G. Giannini. Consen- Class III–IV quality, leading also to statements based on ex- sus Panel: G. Abbruzzese (Chairperson), P. Bower, P. Cortelli, pert opinions. Furthermore, several research gaps emerged P. Martinelli, N. Quinn, E. E. Benarroch, E. Tolosa, and G. K. during the consensus meeting concerning diagnosis, prog- Wenning. Stridor Workgroup: E. Alfonsi, G. Calandra- nosis, and treatment for stridor. Buonaura, I. Ghorayeb, W. G. Meissner (Speaker), T. Ozawa, C. Pacchetti, N. G. Pozzi, and C. Vicini. Dysphagia Workgroup: One main challenge is the diagnosis of stridor. Whether the A. Antonini, K. Bhatia, J. Bonavita, H. Kaufmann (Speaker), M. imitation of stridor by the physician during follow-up visits is T. Pellecchia, N. Pizzorni, A. Schindler, and F. Tison. sufficient to correctly and earlier identify stridor or whether other tools, such as specific questionnaires or a home audio recording, Acknowledgment may improve diagnostic accuracy is unknown. This point could The authors thank Maria Camerlingo (Agenzia sanitaria e be of crucial importance if the negative prognostic role of early sociale regionale, Regione Emilia-Romagna) for assisting in stridor onset is confirmed. It has also to be established when the the search strategy. use of VPSG is necessary for the diagnosis of stridor. For these reasons, a questionnaire for detecting stridor should be de- Study funding veloped and its diagnostic accuracy be compared with VPSG in This study was funded by IRCCS, Istituto delle Scienze a multicenter prospective study. Similarly, the diagnostic accu- Neurologiche di Bologna, Bologna, Italy. racy of sound imitation by the physician or home audio re- cording should be evaluated. A smartphone application could be Disclosure developed to automatically recognize the stridor sound. Finally, P. Cortelli and G. Calandra-Buonaura report no disclosures the place of DISE for early stridor detection requires further relevant to the manuscript. E. Benarroch: Section Editor, investigation, and the method to measure the progression of Neurology. G. Giannini and A. Iranzo report no disclosures stridor over time should be standardized. relevant to the manuscript. P. Low: supported by the NIH (P01NS44233, U54NS065736, R01 FD004789, and R01 The relationship between stridor and other breathing disorders NS092625) and Mayo Funds. P. Martinelli reports no dis- (i.e., central apneas and breathing rate abnormalities) and their closures relevant to the manuscript. F. Provini has received respective contributions to disease prognosis and survival should honoraria for speaking engagements or consulting activities be determined through a multicenter prospective study. VPSG from Sanofi, Bial, Fidia, Vanda Pharmaceuticals, Zambon, should be used to determine stridor and breathing disorders in Eisai Japan, and Italfarmaco. N. Quinn reports no disclosures this study. Moreover, further studies could contribute to elucidate relevant to the manuscript. E. Tolosa received honoraria for the role on survival of specific characteristic obtained from awake consultancy from Novartis, Teva, Bial, Accorda, Boehringer laryngoscopy, DISE, laryngeal EMG (denervation/muscle hy- Ingelheim, UCB, Solvay, Lundbeck, and Biogen and has re- peractivity), and acoustic recordings. In addition, the contribu- ceived funding for research from Spanish Network for Re- tion of stridor to patients and caregiver quality of life is unknown. search on Neurodegenerative Disorders (CIBERNED)–Instituto Carlos III (ISCIII) and The Michael To guide the physician for the treatment of stridor, randomized J. Fox Foundation for Parkinson’s Research (MJFF). G. controlled trials comparing the efficacy of CPAP and trache- Wenning, G. Abbruzzese, P. Bower, E. Alfonsi, I. Ghorayeb, T. ostomy for different degrees of stridor are warranted. Studies Ozawa, C. Pacchetti, N. Pozzi, C. Vicini, A. Antonini, K. using laryngoscopy and/or laryngeal EMG should be conducted Bhatia, J. Bonavita, H. Kaufmann, M. Pellecchia, N. Pizzorni, to identify specific characteristics that may predict treatment A. Schindler, F. Tison, L. Vignatelli, and W. Meissner report tolerance and response. Moreover, the usefulness of CPAP for no disclosures. Outside the present work, W. Meissner has severe stridor, as well as technical aspects including titration, received fees for editorial activities with Springer, for con- patient compliance, and the timing of follow-up need to be sultancy activities from Affiris, Biohaven, Lundbeck, and 638 Neurology | Volume 93, Number 14 | October 1, 2019 Neurology.org/N Sanofi, teaching honoraria from UCB and MDS, and research 26. 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