Laryngological complaint prevalence in hypermobile Ehlers-Danlos or hypermobility spectrum disorders

Abstract

Objective:

To study laryngological complaints in patients with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD).

Methods:

363 patients met inclusion for the study by completing questions related to voice, upper airway, and swallowing between July 7, 2020 and July 13, 2022. Demographic data, voice-related questions and hypermobility diagnosis were analyzed retrospectively. 289 patients were diagnosed with hEDS or HSD with 74 that did not meet the diagnostic criteria for either diagnosis serving as controls.

Results:

There were no statistically significant differences between patients with hEDS and HSD regarding Voice Handicap Index (VHI-10) scores, voice, upper airway or swallow complaints. However, more hEDS/HSD patients answered positively to the laryngeal dysfunction question vs. controls (p=0.031). 22.5% of hEDS/HSD patients (n=65) reported hoarseness, of which 52.3% reported hoarseness >2 days/month. 33.9% (n=98) with hEDS/HSD reported symptoms of dysphagia, and 27.0% (n=78) reported laryngeal dysfunction symptoms. Controls demonstrated 20.3% prevalence of hoarseness, of which 46.7% reported hoarseness >2 days/month. 24.3% of controls had dysphagia and 14.9% laryngeal dysfunction symptoms. Of the 363 patients, VHI-10 scores >11 were more likely in patients reporting >2 days of hoarseness/month (p=0.001) vs. those with <2 days of hoarseness/month. There was an increased prevalence of voice, upper airway, and dysphagia symptoms in hEDS/HSD patients compared to previously reported prevalence data in the general population.

Conclusion:

A significant proportion of patients diagnosed with hypermobility due to hEDS or HSD were found to have voice, upper airway, and dysphagia symptoms. These rates are higher than previously reported in the general population.

Lay Summary:

Patients diagnosed with hEDS or HSD within the EDS Clinic at Mayo Clinic in Jacksonville, Florida were more likely to report hoarseness, swallow difficulty, and laryngeal dysfunction symptoms compared to the previously reported prevalence within the general population.

Level of evidence:

3

Introduction

Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that have been categorized into 13 named subtypes including the symptomatic hypermobility conditions hypermobile EDS (hEDS) and hypermobility spectrum disorders (HSD).¹ EDS is typically characterized by joint laxity, skin hyperextensibility and tissue fragility but also affects multiple systems leading to musculoskeletal, vascular and gastrointestinal symptoms.² Considering the amount of connective tissue in the neck and pharynx, voice, upper airway, and swallowing complaints have been purported to be elevated in patients with EDS compared to the general population. However, few studies have reported laryngological presentations in patients with hEDS/HSD, and these primarily consist of case reports and case series.^3–7

Complaints regarding voice, upper airway, and swallowing can be debilitating, affecting work, home, and social life.⁸ The current study aims to quantify the prevalence of voice, upper airway, and swallowing complaints within the hypermobile population of patients diagnosed with hEDS or HSD presenting to the Mayo Clinic EDS Clinic in Jacksonville, Florida.

Materials and Methods

Ethics Statement

Retrospective review of the demographic and clinical data from the medical records reported in this manuscript was approved by the Institutional Review Board (IRB# 19–011260) and informed consent was waived by the Institutional Review Board for all patients. The research conformed to the principles outlined in the Declaration of Helsinki.

REDCap Database

Patient data related to voice, upper airway, and swallowing concerns were collected from July 7, 2020 through July 13, 2022 using a 200-question REDCap EDS Questionnaire given to patients as standard of care prior to their first appointment at the EDS Clinic. The EDS Questionnaire was used to assist in determining patients that may need referrals to laryngology and speech therapy. Demographic and clinical data related to voice, upper airway, and swallowing were extracted retrospectively from the intake questionnaire from patients that were 18 years or older at their first appointment for use in this study. From the questionnaire, 363 patients from the EDS Clinic met inclusion criteria for the study. Demographic data that were analyzed included gender, age, race, and ethnicity as well as patient diagnosis. Of the 363 patients that were included in the study, 289 were diagnosed with hypermobile hEDS or HSD based on the 2017 International Classification,¹ and the remaining 74 patients did not meet the diagnostic criteria for either diagnosis and served as controls. Patients suspected of having other connective tissue disorders were excluded.

Voice, Upper Airway, and Swallowing Questions

The voice, upper airway, and swallowing questions from the REDCap EDS Questionnaire contained the following four questions:

1. Has hoarseness interfered with your ability to communicate with friends, family, or colleagues? (Yes/No) If Yes, the following question was provided to the patient:

   1. How many days per month has hoarseness caused this problem (< 2 days per month or > 2 days per month) ?

2. Do you cough when you eat or drink more than you cough when not eating or drinking? (Yes/No)

3. Do you experience short-lived episodes of shortness of breath that cause you to make a noise when you breathe in? (Yes/No)

If any of these preliminary questions were answered positively then the patient was prompted to fill out the VHI-10 questionnaire.⁹ Patients with a positive response to question 1 and 1a from the EDS Questionnaire (above) were considered to have complaints of dysphonia. Patients with a positive response to question 2 of the EDS Questionnaire (above) were considered to have symptoms of dysphagia. Finally, patients with a positive response to question 3 of the EDS Questionnaire (above) were considered to have complaints consistent with laryngeal dysfunction. VHI-10 scores for patients with a positive response to the hoarseness questions (“yes” and “more than 2 days per month”) were calculated and analyzed.

Voice, Upper Airway, and Swallowing Complaints in the General Population

We conducted a general review of the literature searching PubMed for articles regarding dysphonia, dysphagia, and dyspnea in the general population using the search terms “prevalence of dysphonia”, “prevalence of dysphagia”, “prevalence of vocal cord dysfunction”, “prevalence of inducible laryngeal obstruction”, and “prevalence of paradoxical vocal fold movement”. We found seven articles that provided data on voice complaints in the general population that were used to compare to patients in this study (Table 1). A more detailed assessment of all data reported in these manuscripts for voice, upper airway, and swallowing complaints in the general population is provided in Supplementary Table 1.

Table 1.

Findings of voice, upper airway, and swallowing complaints in the general population

Year, Author, Reference	Title	Major Findings
1998 Morris et al.24	Vocal cord dysfunction in patients with exertional dyspnea	5 of 33 patients (15.2%) had evidence of vocal cord dysfunction.
2005 Roy et al.20	Voice disorders in the general population: Prevalence, risk factors, and occupational impact	Voice disorder definition: any time the voice does not work, perform, or sound as it normally should, or interferes with communication. 29.9% (n=396)
2007 Wilkins et al.23	The prevalence of dysphagia in primary care patients: A HamesNet Research Network Study	Of the 957 study participants, 21 (22.6%) reported dysphagia a minimum of several times per month.
2012 Cohen et al.19	Prevalence and causes of dysphonia in a large treatment-seeking population	536,943 unique patients who had a dysphonia diagnosis, prevalence rate 0.98%
2014 Bhattacharyya et al.21	The prevalence of dysphagia among adults in the United States	Prevalence of swallowing problems: 4.0% ± 0.1% of the adults US population.
2015 Cho et al.22	Prevalence and risk factors for dysphagia: a USA community study	The overall dysphagia in the prior year was 19.5% (95% CI 18.2–20.8).
2017 Benninger et al.18	Prevalence and occupation of patients presenting with dysphonia in the United States	Prevalence estimates and compound annual growth rates (CAGR) for all conditions from 2008 to 2012: 13.2%

Statistical Analysis

Statistical analysis was completed using R3.6.2. Categorical variables were summarized as frequency (percentage) and continuous variables were reported as median (range) and mean (standard deviation/SD). Wilcoxon signed rank test or Kruskal-Wallis test was used to evaluate the difference in continuous variables between groups. Chi-squared test or Fisher’s exact test was used to test the difference of categorical variables between groups. All tests were two-sided with a p value < 0.05 considered statistically significant.

Results

Demographics

From 363 patients that conducted the REDCap EDS Questionnaire for questions related to voice, upper airway and dysphagia, 11.3% were diagnosed with hEDS (n = 41), 68.3% with HSD (n = 248) and 20.4% were controls (n = 74) (Table 2). Most patients were female (p = 0.006): 78% hEDS, 93.5% HSD and 87.8% of controls (Table 2). 4.9% of hEDS and 2.8% of HSD patients identified as non-binary. Most patients were White with 92.7% of hEDS patients, 94.4% HSD and 95.9% of controls self-reporting this race (Table 2).

Table 2.

Demographics

	hEDS (n=41)	HSD (n=248)	Controls (n=74)	P value
Gender				0.001
Female	32 (78.0%)	232 (93.5%)	65 (87.8%)
Male	7 (17.1%)	9 (3.6%)	9 (12.2%)
Non-binary	2 (4.9%)	7 (2.8%)	0 (0.0%)
White	38 (92.7%)	234 (94.4%)	71 (95.9%)	0.72
American Indian/Alaskan native	0 (0.0%)	4 (1.6%)	1 (1.4%)	1.00
Asian	1 (2.4%)	1 (0.4%)	0 (0.0%)	0.26
Black/African American	3 (7.3%)	6 (2.4%)	3 (4.1%)	0.20

Voice, Upper Airway, and Swallowing Data

The control group was comprised of patients seeking evaluation in the EDS Clinic for their symptoms, but who were not diagnosed with hEDS nor HSD. This group of 74 patients demonstrated a 20.3% prevalence of hoarseness, of which 46.7% reported hoarseness more than 2 days per month (Table 3). Controls also demonstrated a positivity rate of 24.3% and 14.9% for dysphagia symptoms and laryngeal dysfunction, respectively (Table 3).

Table 3.

Combined hEDS/HSD vs. control voice answers to EDS Questionnaire

	hEDS/HSD (n=289)	Control (n=74)	Total (n=363)	P value
Has hoarseness interfered with communication?				0.68
No	224 (77.5%)	59 (79.7%)	283 (78.0%)
Yes	65 (22.5%)	15 (20.3%)	80 (22.0%)
If yes, less than 2 days, or more than 2 days per month?				0.69
No VHI-10 score	224	59	283
Less than 2 days per month	31 (47.7%)	8 (53.3%)	39 (48.8%)
More than 2 days per month	34 (52.3%)	7 (46.7%)	41 (51.2%)
Do you cough more when eating/drinking than when not eating/drinking?				0.12
No	191 (66.1%)	56 (75.7%)	247 (68.0%)
Yes	98 (33.9%)	18 (24.3%)	116 (32.0%)
Do you experience short-lived episodes of shortness of breath that cause you to make a noise when you breathe in?				0.031
No	211 (73.0%)	63 (85.1%)	274 (75.5%)
Yes	78 (27.0%)	11 (14.9%)	89 (24.5%)

Of the 289 patients diagnosed with hEDS or HSD who completed the voice, upper airway, and dysphagia questions on the intake questionnaire, 22.5% (n = 65) reported that hoarseness affected their ability to communicate compared to 20.3% (n = 15) of controls (p = 0.68) (Table 3). 52.3% of patients with hEDS/HSD that affirmed hoarseness reported that it affected their ability to communicate on more than 2 days per month vs. 46.7% of controls (p = 0.69) (Table 3). 33.9% (n = 98) of hEDS/HSD patients reported signs and symptoms of dysphagia (coughing more when eating or drinking than when not eating or drinking) compared to 24.3% (n = 18) of controls (p = 0.12) (Table 3). 27.0% (n = 78) of the hEDS/HSD group also affirmed symptoms of laryngeal dysfunction compared to 14.9% of controls (n = 11) (p = 0.031) (Table 3). Data examining answers to the same questions for hEDS vs. HSD vs. controls are shown in Table 4.

Table 4.

hEDS vs HSD vs controls voice answers to EDS Questionnaire

	hEDS (n=41)	HSD (n=248)	Control (n=74)	P value
Has hoarseness interfered with communication?				0.21
No	36 (87.8%)	188 (75.8%)	59 (79.7%)
Yes	5 (12.2%)	60 (24.2%)	15 (20.3%)
If yes, more or less than 2 days per month				0.52
No VHI-10 Score	36	188	59
Less than 2 days per month	1 (20.0%)	30 (50.0%)	8 (53.3%)
More than 2 days per month	4 (80.0%)	30 (50.0%)	7 (46.7%)
Do you cough more when eating/drinking?				0.11
No	31 (75.6%)	160 (64.5%)	56 (75.7%)
Yes	10 (24.4%)	88 (35.5%)	18 (24.3%)
Do you experience short-lived episodes of shortness of breath that cause you to make a noise when you breathe in?				0.079
No	29 (70.7%)	182 (73.4%)	63 (85.1%)
Yes	12 (29.3%)	66 (26.6%)	11 (14.9%)

VHI-10 Scores

Of the hEDS/HSD patients that affirmed hoarseness affected their ability to communicate more than 2 days per month (Table 3), 83.9% had a VHI-10 score of greater than 11 indicating functional deficits related to voicing (Table 5). Additionally, VHI-10 scores for patients who affirmed hoarseness were more likely to be above the normal threshold of 11 (p = 0.001). The difference in VHI-10 scores between hEDS/HSD vs. controls (p = 0.95) or hEDS vs. HSD vs. controls (p = 0.94) was not statistically significant (Table 5, Table 6). Importantly, controls had higher VHI-10 scores than the hEDS/HSD patients in this study. But controls in this study were sick patients that were seen in the EDS Clinic, which may explain why they had many voice, upper airway, and swallowing complaints. Thus, although these patients that were not diagnosed with hEDS/HSD were a unique type of control having undergone all the same assessments, they turned out to not be an ideal control group to compare to hEDS and HSD patients. For this reason, we also examined studies from the literature to understand the prevalence of dysphonia, dysphagia, and laryngeal dysfunction symptoms in the general population.

Table 5.

VHI-10 scores in hEDS/HSD vs. controls

	hEDS/HSD (n=289)	Control (n=74)	Total (n=363)	P value
VHI total				0.95
N	39	7	46
Median (Range)	16.0 (0.0, 30.0)	14.0 (0.0, 40.0)	15.5 (0.0, 40.0)
Mean (SD)	15.2 (7.4)	16.7 (12.3)	15.4 (8.2)

Table 6.

VHI-10 Scores in hEDS vs. HSD vs. controls

	hEDS (n=41)	HSD (n=248)	Control (n=74)	P value
VHI total				0.73
N	3	36	7
Median (Range)	19.0 (15.0, 20.0)	15.5 (0.0, 30.0)	14.0 (0.0, 40.0)
Mean (SD)	18.0 (2.6)	14.9 (7.7)	16.7 (12.3)

The 30-question VHI allows for easy sub-scoring of functional, physical, and emotional sub-scores. While the VHI-10 does not typically include these sub-scores, it is easy to discern to which sub-score each statement of the VHI-10 belongs, as the VHI-10 was validated after the VHI-30 and is extracted from the VHI-30. The VHI-10 encompasses 5 “functional” statements, 3 “physical” statements, and 2 “emotional” statements. Each statement is rated on a scale from 0 (“Never”) to 4 (“Always). hEDS and HSD patients who completed the VHI-10 for this study had an average score of 1.54 on functional statements, 2.23 on physical statements, and 1.75 on emotional statements.

Voice complaints in the general population vs. hEDS/HSD patients from Mayo EDS Clinic

An assessment of the literature for hEDS/HSD manuscripts revealed several case reports and observational studies demonstrating voice, upper airway, and swallow complaints in patients with hEDS and/or HSD (Supplemental Table 2).^{3–7,10–20} There were also recent descriptions of the laryngological findings of Laryngology Clinics who see numerous patients with hEDS/HSD (Supplemental Table 2).^21,22 The primary symptoms identified in a recent study of 20 diagnostically-confirmed hEDS patients were swallowing (70%) and voice (42%).²¹

An assessment of the literature for voice disorders in the general population estimated the prevalence to be between 0.98% to 6.6% (Table 1, Supplementary Table 1).^8,23,24 The prevalence of swallow disorders in the general population has been estimated to be 3–23% (Table 1, Supplementary Table 1).^25–27 Finally, the prevalence of upper airway complaints (i.e., laryngeal dysfunction/paradoxical vocal fold movement) in the general population is sparsely reported, but has been postulated to be 2.8% to 15.2% (Table 1, Supplementary Table 1).²⁸

In contrast to the estimated prevalence range of these conditions in the general population, hEDS/HSD patients in this study had higher dysphonia symptoms (22.5% vs. 0.98%−6.6%), higher laryngeal dysfunction symptoms (27% vs. 2.8–15.2%), and higher dysphagia symptoms (33.9% vs. 3–23%) (Table 7).

Table 7.

Percentage of voice issues in the general population vs. hEDS/HSD patients presenting to the Mayo EDS Clinic

Symptom	Estimated in the general population*	hEDS/HSD patients
Dysphonia	0.98–6.6%	22.5%
ILO symptoms	3–23%	27%
Dysphagia	2.8–15.2%	33.9%

^*see Table 1 and Supplementary Tables 1 and 2 for references.

Abbreviations: ILO, inducible laryngeal obstruction

Discussion

While it has certainly been postulated that there is an increase in voice, upper airway, and swallow pathologies within the hEDS/HSD population,^16,21 there are no studies reporting a prevalence rate of these symptoms within a diagnostically confirmed hEDS or HSD population. The results of this study do not indicate an increased prevalence of reported dysphonia, dyspnea, and dysphagia symptoms in patients with a formal diagnosis of hEDS or HSD compared to internal controls from the Mayo Clinic EDS Clinic. The control group was comprised of patients who required work-up for hEDS/HSD, but ultimately did not receive this diagnosis. Differential diagnoses for these patients may include fibromyalgia, other connective tissue disorders, autoimmune disease, chronic regional pain syndrome, or others. Given these controls report similar symptoms as patients with hEDS/HSD, it is perhaps not surprising that they present with similar voice, upper airway, and dysphagia symptoms. Thus, they do not appear to be an ideal control population to determine the prevalence of voice issues in hEDS and HSD patients. Only one question regarding voice/upper airway symptoms was statistically different between patients with hEDS/HSD and controls; the question regarded short-lived episodes of shortness of breath that cause a noise when breathing in (laryngeal dysfunction symptoms). This finding is interesting and should be explored in future research. Future studies will need to compare the symptoms of patients with a confirmed diagnosis of hEDS/HSD to patients that do not have voice issues. For this reason, we searched the literature for estimates of the prevalence of these complaints in the general population. Upon comparison, there is an evident increase in the prevalence of voice, upper airway, and dysphagia symptoms observed in hEDS/HSD patients from our EDS Clinic compared to what has been reported for the general population (Table 7).

Another major finding of this study was that there were no significant differences in the prevalence of voice, upper airway, dysphagia symptoms, or VHI-10 scores between patients with HSD or hEDS. This suggests that patients with symptomatic hypermobility experience similar voice, upper airway, and swallow symptoms. Although the 2017 diagnostic criteria distinguish hEDS from HSD from each other, many comorbidities are shared between the two conditions. Our data suggest that voice, upper airway, and swallow issues may also be experienced similarly between the conditions. Future studies should examine this question in more detail.

As mentioned above, VHI-10 scores do not typically provide sub-scores for functional, physical, and emotional impacts; however, it is possible to assign the 10 statements on this questionnaire to these categories based on the same categories the questions fall into on the VHI-30. The “physical” statements on the VHI-10 describe a need to “strain to produce voice,” being asked “What’s wrong with your voice?” and unpredictable vocal clarity. “Functional” statements on the VHI-10 review complaints of difficulty with projection, personal/social life restrictions, feeling “left out of conversations,” and income loss. Finally, “emotional” statements address feeling upset or handicapped related to voice issues. In comparing functional, physical, and emotional statement types of the VHI-10, we found that physical scores were rated the highest and functional scores were rated the lowest with emotional scores falling somewhere in between. This suggests patients with hEDS and HSD are more likely to experience physical effects on the voice more than functional or emotional effects.

This study has a number of limitations. The unique internal controls in the EDS Clinic that were not diagnosed with hEDS or HSD but shared similar systemic symptoms turned out to have a high percentage of laryngological symptoms and were thus not ideal controls. This made it difficult to evaluate the severity/prevalence of laryngological issues in our hEDS/HSD population. In future studies we will need to examine a more suitable control group for comparison. Another limitation to the study is that we asked only several brief questions to assess voice dysfunction in our intake questionnaire. The current EDS clinic intake questionnaire has 200 questions and so additional laryngological questions were not able to be added. Future studies should provide patients that express laryngological concerns with more extensive questionnaires such as the Dyspnea Index,²⁹ Cough Severity Index,³⁰ and Eating Assessment Tool-10.³¹ The laryngological questions in our intake questionnaire help guide appropriate referrals to the laryngology clinic, and therefore, are not formal questionnaires. More research is needed to further qualify voice, upper airway, and swallowing concerns within the hEDS/HSD population. Further research should also address the concomitant factors that may lead to these symptoms in patients with hEDS/HSD. Additionally, research into appropriate voice, airway and swallow treatment modalities/therapy for patients with hEDS or HSD should also be explored.

Conclusion

Overall, our study found that a significant proportion of patients diagnosed with hEDS or HSD self-reported voice, upper airway, and/or dysphagia symptoms. These rates in hEDS/HSD patients were higher than prevalence data reported for the general population.

Supplementary Material

Supinfo

1. Supplemental Table 1. Findings of voice, upper airway, and swallowing complaints in the general population

2. Supplemental Table 2. Previously published case reports, observational studies, and laryngeal findings for voice, upper airway, and swallowing complaints in patients with EDS, hEDS and/or HSD