Exercise-induced Paradoxical Vocal Fold Motion Disorder: Clinical Features and Potential Mechanisms
Condition: Disorder of Vocal Cord
MeSH terms: Vocal Cord Dysfunction
Study type: Interventional

Summary: 
      Exercise-induced paradoxical vocal fold motion disorder (E-PVFMD) - which severely impacts
      the lives of up to 1 million adolescents in the U.S. annually - is under- or mis-diagnosed in
      as many as 80% of cases, leading to ineffective, protracted periods of management.
      Additionally, what makes those with the condition different from those at risk for the
      condition (e.g., playing sports/engaging in athletic activity within a competitive athletic
      environment) is unclear. The goals of this proposed study are to address this diagnostic
      challenge by (1) pursuing a previously published preliminary taxonomic algorithm for the
      clinical identification and classification of EPVFMD, and by (2) elucidating potential
      underlying mechanisms driving this clinical presentation. Study outcomes will improve
      sensitivity and specificity of diagnosis protocols for PVFMD, thereby reducing prevalence of
      misdiagnosis and improving clinical management in individuals with this disorder in the
      future. Outcomes will also be used to create preventative care measures for adolescents at
      risk for the condition.
    

Detailed description: 
      The experimental protocol consists of five stages in total (Stages IV): (1) Screening, (2)
      Pre-Baseline, (3) Baseline Laryngoscopy Condition, (4) Exercise Laryngoscopy Condition, and
      (5) Recovery. The following sections describe procedures conducted within each of the five
      stages

      Stage I: Screening

      To determine eligibility, all consenting participants will (1) undergo spirometric screening
      to rule out any indication of pulmonary pathology, (2) report they partake in athletic
      activity within a competitive environment (self-perceived/reported), and (3) complete the
      Dyspnea Index (DI). Participants with less than 80% predicted FEV1 on spirometry will be
      excluded from the study and referred to the pediatric pulmonary clinic at Massachusetts
      General Hospital (MGH). Anyone who reports they feel their sports-related activities are not
      competitive will be excluded. Participants in the E-PVFMD group who score less than 10 out of
      40 on the DI will be excluded from the study, whereas participants in the at-risk group who
      score more than 6 out of 40 on the DI will be excluded from the study.

      Stage II: PreBaseline

      All participants who have passed the screening will rate the worst severity of perceived
      shortness of breath experienced during the screening period, as well as other symptoms
      relating to PVFMD (i.e., cough, globus, dysphonia, laryngeal pain/tension), on a 0100mm
      visual analog scale (VAS). These values will later serve as anchors for subsequent symptom
      ratings. Rating severity of symptoms prior to laryngoscopy will also prime participants for
      symptom severity ratings in subsequent conditions, described shortly in detail. Next, blood
      pressure (SBP) and heart rate (HR) readings will be obtained three times (x3) at 30-second
      intervals or greater over a 5minute period, using a blood and heart rate monitor. The three
      readings will then be averaged and used as anchors for SBP and HR readings taken during
      subsequent study phases. Two self-reported questionnaires will then be administered to all
      enrolled participants: the Early Adolescent Temperament Questionnaire - Revised-short form
      (EATQ-R-SF) and the Paffenbarger Physical Activity Questionnaire (PPAQ). Participants will
      read and complete the two questionnaires on their own, although the PI or parent/guardian may
      clarify questions or help participants read instructions, especially with younger
      participants. Last, a respiratory transducer band will be placed on ribs 5-8 to measure
      respiratory rate (RR) and tidal volumes (TV). These parameters may be used to stratify/bin
      data, posthoc.

      Stage III: Baseline Laryngoscopy Condition

      Participants will be positioned upright in an examination chair and given a decongestant
      (e.g., Afrin®) in one nasal passage. The laryngeal vestibule will then be visualized with
      flexible nasoendoscopy (laryngoscopy) using halogen light. Subjects with structural or
      dynamic abnormalities occluding more than a third of the airway will be ruled out (and
      excluded, as needed) and normal laryngeal movement (i.e., abduction on inspiration and slight
      adduction on exhalation) will be confirmed at rest by both clinician and ENT physician. The
      laryngeal examination will then be recorded and glottic and supraglottic laryngeal
      configuration will be analyzed later offline. The PI will watch the participant's thoracic
      and abdominal cavity movement and will call the beginning of each inspiratory ("I") and
      expiratory ("E") phase as the participant breathes. The calls will be recorded on laryngeal
      examination videos and used to identify optimal periods within specific phases of the
      respiratory cycle from which to extract digital still images of the larynx. Participants will
      be asked to remain as relaxed as possible, but instructions will not relate to breathing so
      as not to bring attention to respiratory patterns. Three SBP and HR readings will be recorded
      for the second time with a blood pressure cuff every 30 seconds or more over a 5min period
      and averaged across the three trials. Once the endoscope has been removed, participants will
      be asked to rate perception of their worst severity of shortness of breath experienced during
      the baseline laryngoscopy condition on the 0-100mm VAS for the second time.

      Stage IV: Exercise Laryngoscopy Condition

      Participants will then undergo a graded exercise test (GXT) with cycle ergometer and
      simultaneous flexible laryngoscopy. The exercise challenge will parallel procedures in a
      previously described 1minute progressive incremental cycle ergometer protocol, starting at 50
      watts (300 kgm/min), with increments of 50 watts every minute. Simultaneous laryngoscopic
      procedures, as well as SBP and HR recordings, will generally parallel those of the baseline
      laryngoscopic protocol in Stage III. To minimize risk of injury or overexertion, explicit
      instructions for the exercise protocol will be given to each participant prior to the start
      of the protocol. Once participants have communicated understanding, they will sit on the
      ergometer and the seat will be properly adjusted so there is a slight bend in the knee joint
      when the ball of the foot is on the pedal, with the pedal in its lowest position (~10-15°
      angle of knee flexion when the leg is extended). Once seated in position, participants will
      be instructed to relax the grip of the handlebar to prevent peripheral constriction, which
      could confound cardiovascular functions. The blood pressure cuff will be adjusted accordingly
      in the standard fashion and a pulse oximeter will be fitted on the participant's middle
      finger of the dominant hand to monitor oxyhemoglobin saturation during the exercise
      challenge. Participants will then be trained on rating perceived levels of exertion by
      pointing to the Borg Perceived Exertion Scale mounted on a board. The Borg scale goes from 6
      to 20, where 6 represents no feelings of exertion and a score of 19 represents anaerobic
      activity that cannot be sustained for more than a minute. Borg severity ratings will be used
      to identify optimal level of exertion for measures extracted from video images during the
      exercise condition. During this task, participants will be encouraged not to vocalize and
      will be asked to rely solely on the board to communicate their perceived level of exertion
      for each incremental exercise load that will be imposed. The goal of this endeavor is to
      avoid movement of the vocal folds with vocalization, which may confound respiratory
      (non-phonatory) laryngeal configuration parameters. A head mount will then be placed on the
      participant's head and the head of the flexible endoscope will be inserted into the head
      mount, with the flexible camera dangling from the head mount below the head of the endoscope.
      Next, participants will be reminded of the Borg Scale ratings, and re-instructed as needed.
      For participants with potential E-PVFMD, instructions will also be provided to indicate
      induction of PVFMD attack with a "thumbs up" signal during the provocation challenge. All
      participants will be informed they will be encouraged to continue pedaling throughout the
      protocol until vigorous exercise levels are reached. Participants will also be reminded the
      protocol is voluntary and they can terminate the trial at any time. Once participants have
      communicated understanding and their willingness to continue, the flexible camera lens will
      once again be inserted into the same nostril, in the same manner as for the baseline
      laryngoscopy examination. Once the laryngeal vestibule has been identified with the
      laryngoscope, the flexible camera lens will then be secured to the ipsilateral nare with
      surgical tape to prevent movement of the scope in and out of the nose. The graded exercise
      test (GXT) will then begin at 50 watts (300 kgm/min) with target increases of 300 kgm/min
      every minute, per standard GXT protocol. Participants will be asked to maintain a 50-70 RPM
      pedal rate (displayed on the ergometer) with each incremental increase in load. For
      participants in the E-PVFMD group, incremental loads will continue until one of two events
      transpires: (1) E-PVFMD attack occurs (i.e., the participant experiences symptoms
      representative of previously experienced paroxysmal PVFMD episodes, and indicates induction
      of the episode with a "thumbs up" sign). Once the episode begins, videoendoscopy recordings
      will be obtained for an additional 30 seconds before the exercise laryngoscopy challenge is
      terminated, at which point the video recording will also be stopped. (2) No signs/symptoms of
      "attack" occur at the 3-minute mark with maximum exertion (19-20 Borg score), and the
      challenge is terminated. Results in these latter cases will be binned for future analysis
      beyond the scope of the proposed study. However, the sans-PVFMD-attack cohort in the PVFMD
      group will be excluded from analysis for the final n=25 in the present study and replaced
      until the targeted sample size (n = 25) has been reached. For the at-risk group, once a score
      of 19 on the Borg scale has been reported, 30 additional seconds of videoendoscopy will be
      recorded before the task is terminated. To terminate the protocol for both groups, the bike
      ergometer will first be reduced to 0 watts load and the laryngoscope will be removed from the
      nasopharynx. During the exertion task, SBP and HR will be recorded at the one minute mark,
      right before each additional incremental increase in load, and then again 1-2 times during
      maximum exertion (Borg scale 19-20) within the 30-second maximum exercise challenge (and
      subsequent videoendoscopic recording time frame). Participants will be on the bike a maximum
      of 10 minutes.

      Stage V: Recovery

      The cycle ergometer task will be stopped and SBP and HR will once again be recorded, this
      time at the 1-minute, 2-minute, and 3-minute post-max exertion time points, determined by a
      stopwatch. Participants will be asked to rate their worst perceived symptoms experienced
      during the exercise laryngoscopy task for the third (and final time) time using the 0-100
      VAS. HR readings will then be used to calculate heart rate recovery (HRR) offline for further
      data analysis. Participants will then cycle for an additional 1-2 min for proper cool down to
      ensure cardiovascular parameters are back to baseline before they are helped off the bike.
    

Intervention name(s): Diagnostic Study
Intervention type(s): Behavioral
Intervention description(s): Participants will undergo laryngoscopy at baseline and with exercise challenge and will rate severity of various symptoms related to the larynx (ex. shortness of breath, voice changes, cough).
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Diagnostic