Management of Chronic Laryngopharyngeal Neuropathy in the United States and Europe

Introduction

Patients with laryngopharyngeal symptoms are familiar to specialty trained otolaryngologists. These patients endorse a myriad of symptoms, which include cough, hoarseness, throat clearing, foreign body sensation, throat pain, sensation of excessive phlegm, and difficulty swallowing. The physical examination in many of these patients does not provide a definitive etiology. The differential for such patients includes laryngopharyngeal reflux (LPR; defined at gastric content reflux into the laryngopharynx), rhinosinusitis-induced postnasal drainage, direct allergic effect, smoking, and other environmental causes.

A large number of patients present with chronic cough and laryngopharyngeal symptoms, but a subset of patients fail to improve on empirically prescribed medications. These medications most commonly involve those targeting reflux but can also include medications for suspected cough-variant asthma and postnasal drip. It was originally postulated that such patients had an “irritable larynx” with a postviral neuropathic component to its pathophysiology.^1-2 Given that such patients report neuropathic symptoms of the laryngopharynx, the term chronic laryngopharyngeal neuropathy (CLPN) has also been proposed as a better term to describe this myriad of symptoms. ³ It has also been suggested that these patients have a centrally regulated overreaction to sensory stimuli, resulting in laryngospasm, cough, and dysphonia. These patients have been shown to have higher rates of irritable bowel syndrome, fibromyalgia, and chronic fatigue syndrome, which supports this theory. ⁴ Evidence also suggests that these patients can significantly benefit from antineuralgia medications.^5-9 However, CLPN is still not a proven entity. There is no objective test for CLPN and the diagnosis is often one of exclusion after multiple treatments have been tried. ¹⁰ Despite the above findings, there is still no randomized trial comparing placebo to antineuralgia medications for CLPN.

The concept that a neuropathic cause may be responsible for chronic laryngopharyngeal symptoms is a relatively new development that has been researched predominantly by fellowship-trained laryngologists in the United States. Few European researchers have investigated this topic, and it is therefore unknown if the same level of awareness regarding this condition has reached the international laryngology community. We surveyed members of the American Laryngological Association (ALA) and the European Laryngological Society (ELS) to determine whether there are differences in the practice patterns and knowledge of CLPN between the 2 societies.

Materials and Methods

Approval for this study was obtained from the Boston University Medical Center Institutional Review Board. An online survey (Appendix A) was emailed to all 179 active members of the ALA and all 324 members of the ELS with valid email addresses using Survey Monkey (www.SurveyMonkey.com). The survey collected information concerning awareness of CLPN, work-up of CLPN patients, and preferred treatments. Four weeks after the initial surveys were sent, nonresponders in both groups received a second email. A third and final email was sent approximately 8 weeks after the initial mailing. Participation was voluntary and confidential. Respondents consented to be in the study by completing the survey. Surveys that were returned blank were not included as responses. Descriptive information about years in practice, practice setting, and primary specialty was collected. There were also questions regarding CLPN, including assessment of knowledge, diagnosis, and treatment.

Fellowship training in laryngology is uncommon in Europe, which made it difficult to determine the number of laryngologists within the ELS. To select out practitioners who predominantly practiced laryngology, we defined ELS laryngologists as practitioners with a laryngology-oriented practice (defined as greater than 50% of their practice). For ALA members, respondents who identified laryngology as their primary area of practice and were fellowship trained were considered laryngologists. Statistical analysis was performed using SAS 9.1 (SAS Institute, Cary, North Carolina, USA). Time in practice for the ALA group was compared to the ELS group using a 2-sample t test. Training and specialty characteristics between the 2 groups were analyzed using a 2-tailed Fisher exact test due to small numbers. Likert scale questions that asked providers to rate their agreement on a scale of 1 (minimum) to 7 (maximum) were treated as non-normal and compared using Wilcoxon rank sum.

Results

Responses from a total of 19 questions were collected. In the ALA group, 40 of the 179 potential respondents completed the survey (23.3%), with 31 of 40 respondents identifying laryngology as their primary area of practice. In the ELS group, 72 of 324 potential respondents completed the survey (22.2%). Results from 7 ELS respondents who work primarily in the United States or a non-European country were excluded from subsequent analyses. Of the 65 ELS respondents who work in Europe, 37 described spending 50% or more of their practice time on laryngology. The average number of years in practice for ALA laryngologists was 14.9 compared to 20.1 for ELS laryngologists. Among ALA laryngologists, 83.9% described working in an academic setting, compared to 89.2% of ELS laryngologists. A total of 25 ALA laryngologists (n = 25) was fellowship trained in laryngology (80.6%). In comparison, 81.1% of ELS laryngologists (n = 30) stated that they received fellowship or equivalent training in laryngology or associated subspecialties. Of these respondents, 70.3% specifically described additional training in laryngology (n = 26), and 13.5% reported training in phoniatrics (n = 4) and/or phonosurgery (n = 1) (Table 1). Within the comments section of the survey, 2 ELS laryngologists noted the absence of fellowship training or subspecialization in their country of practice.

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Table 1.

Demographics of ALA and ELS Respondents.

	ALA	ELS	P Value
Response rate	40/179 = 23.3%	72/324 = 22.2%	1.0000
Laryngologists	31/40 = 79.5%	37/65 = 56.9%	0.0371
Laryngologists with fellowship-level training in laryngology a	80.6%	81.1% a	1.0000
Laryngologists working in academic setting	83.9%	89.2%
Average no. of years in practice for laryngologists	14.93	20.06	0.0169 (Wilcoxon rank sum 2-tailed)

Abbreviations: ALA, American Laryngological Association; ELS, European Laryngological Society.

a

Fellowship training in laryngology is uncommon in Europe. To select out practitioners who predominantly practiced laryngology, we defined laryngologists as ELS members with a laryngology-oriented practice (defined as greater than 50% of their practice). For ALA members, respondents who identified laryngology as their primary area of practice and were fellowship trained were considered laryngologists.

When asked how they had learned about CLPN, no respondents in the ALA group reported being unfamiliar, compared to 7 respondents (18.9%) in the ELS group who reported being unfamiliar with the diagnosis (P < .01). Both ALA and ELS laryngologists cited peer-reviewed journals and conferences as the most common sources for information about CLPN. However, whereas 77.4% of ALA laryngologists also learned about CLPN from colleagues, only 17.1% of ELS laryngologists reported doing so (P < .01) (Table 2).

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Table 2.

Response to the Question, “I am aware of the diagnosis and management of laryngeal neuropathy from the following sources.”

Source of Information About Laryngopharyngeal Neuropathy	ALA	ELS	P Value (Fisher)
Peer-reviewed journals	96.8%	65.7%	.0008
Residency training	51.6%	8.6%	.0001
Colleagues	77.4%	17.1%	< .0001
Conferences	90.3%	60%	.0026
Not familiar with diagnosis (or no response)	0%	18.9%	.0133

Abbreviations: ALA, American Laryngological Association; ELS, European Laryngological Society.

Respondents were then asked to answer on a 7-point Likert scale how comfortable they were in making the diagnosis of CLPN. Laryngologists from the ALA reported an average comfort level of 6.3 (SD 0.7) versus 4.3 for ELS laryngologists (SD 1.7) (P < .01) (Figure 1). In response to a question assessing which etiologies practitioners were most likely to attribute to laryngopharyngeal symptoms, there were no significant differences noted between the groups with the exception of laryngopharyngeal neuropathy (P < .01) (Table 3). Furthermore, both groups were most likely to attribute gastroesophageal reflux disease (GERD) as the cause of laryngopharyngeal symptoms. In response to a question regarding the potential overdiagnosis of laryngopharyngeal reflux (LPR; defined as gastric contents refluxing into the laryngopharynx) in patients with laryngopharyngeal symptoms, 48.4% of ALA laryngologists felt that LPR was overdiagnosed compared to 73.0% of the ELS laryngologists (P < .05).

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Figure 1.

Response to the question, “I feel comfortable diagnosing someone who may have chronic laryngopharyngeal neuropathy” (question 6).

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Table 3.

Response to Likert (0-7) Scale Question, “I feel comfortable diagnosing someone who may have. . . .”

ALA	Average	ELS	Average	P Value
GERD/LPR	5.4	GERD/LPR	5.5	.778
Laryngeal neuropathy	4.5	Laryngeal neuropathy	3.0	.00046
Allergies/rhinitis	3.2	Allergies/rhinitis	2.9	.44
Viral URI	3.2	Viral URI	3.2	.87
ACE inhibitor	3.0	ACE inhibitor	2.6	.352
Dystonia	1.8	Dystonia	2.1	.177

Abbreviations: ACE, angiotensin-converting-enzyme; ALA, American Laryngological Association; ELS, European Laryngological Society; GERD, gastroesophageal reflux disease; LPR, laryngopharyngeal reflux; URI, upper respiratory tract infection.

Respondents were asked about their next steps in management in a patient with CLPN. Laryngologists from the ALA were significantly more likely to start neuromodulator agents versus ELS laryngologists (90.3% vs 48.6%) (Table 4). Regarding specific neuromodulator agents, ALA laryngologists were significantly more likely to start amitriptyline. A significant proportion of ELS laryngologists were not familiar with various neuromodulator agents (Table 5).

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Table 4.

Response to the Question, “In an adult patient who presents with chronic cough and globus, what is/are your next step(s) in management/evaluation?”

	American Laryngologists	European Laryngologists	P Value (Fisher)
Antineuralgia medications	90.3%	48.6%	0.0001
PPI treatment	41.9%	62.9%	0.2231
Voice therapy	51.6%	42.9%	0.4646
Oral steroids	9.7%	17.1%	0.4940
H2 blockers	9.7%	17.1%	0.4940
Allergy medication	6.5%	8.6%	1.0000
Surgery	3.2%	0.0%	0.4559
Antibiotics	0.0%	0.0%	1.0000

Abbreviation: PPI, proton pump inhibitor.

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Table 5.

Response to the Question, “What are the most common modalities you use to treat adult patients with laryngeal neuropathy?”

	American Laryngologists	European Laryngologists	P Value
Amitriptyline	58.6%	27.8%	0.0261
Gabapentin (Neurontin)	31.0%	16.7%	0.2482
Nortriptyline	3.4%	5.6%	1.0000
Pregabalin (Lyrica)	3.4%	2.8%	1.0000
I am not familiar with this medication	3.4%	47.2%	0.0001

Discussion

The data show that there are clear differences in the diagnosis, workup, and treatment of patients with chronic laryngopharyngeal symptoms between European and American laryngologists. There was a difference in awareness, with 7 respondents (18.9%) in the ELS group reporting being unfamiliar with the concept of chronic laryngopharyngeal neuropathy, compared to 0 respondents (0%) in the ALA group. This suggests either that information regarding the concept of chronic laryngopharyngeal neuropathy is not reaching European laryngologists or that the academic leaders of the ELS are more skeptical of CLPN as a diagnosis. In addition, this American bias may be due to the fact that this disorder was originally postulated by members of the ALA, and therefore, more of their colleagues have followed suit in investigating and learning about this disorder. Regardless of the reason for this difference, provider education and research into laryngopharyngeal symptoms may benefit a subset of patients by reducing unnecessary treatments and evaluations and decreasing exposure to side effects of prolonged proton pump inhibitor (PPI) usage. ¹¹

Although no objective test to verify the diagnosis of CLPN exists and the disorder itself is primarily based on clinical information, research has suggested a benefit from the use of neuromodulating agents in some patients with laryngopharyngeal symptoms. A 10-mg daily dose of amitriptyline has been shown to be more effective than codeine-guaifenesin in reducing cough resulting from postviral vagal neuropathy. ⁶ In patients with suspected laryngopharyngeal neuropathy, it has also been shown to decrease self-reported symptoms of cough by at least 40%. ⁴ Its beneficial effect is further supported by a recent systematic review of the evidence for the use of the neuromodulating agents amitriptyline, gabapentin, pregabalin, and baclofen for neuropathic cough. ¹² However, it should be noted that no randomized clinical trials comparing neuromodulating agents to placebo in patients with suspected CLPN have been conducted. Given the dramatic influence that the placebo effect can have on cough, ¹³ CLPN cannot be verified as a true diagnosis without a direct comparison study. The CLPN literature would likely benefit from the help of European investigators, who could provide a different approach to investigating CLPN and clarifying the effect on the chronic cough population as a whole. Indeed, the inclusion of our European colleagues in this study attempts to begin such a dialogue.

It is interesting that 48.4% of ALA laryngologists felt that LPR was overdiagnosed in patients with laryngeal symptoms compared to 73% in the ELS group (P < .05). This suggests that European physicians are less likely to continue antireflux medications and to pursue additional testing in the setting of persistent symptoms and could be open to alternate diagnoses. In fact, patients with chronic laryngeal symptoms are often started on high-dose PPI therapy, and this diagnosis is sometimes abandoned after symptoms fail to improve. Recently, there has been evidence suggesting that further workup with multichannel intraluminal pH impendence and high-resolution esophageal manometry may be warranted before ruling out LPR in patients who have failed PPIs. ¹⁴ To further complicate matters, the 2 syndromes of LPR and CLPN may be coexistent in some patients. Treatment may thus be determined on the strength of evidence from pH impedance and manometry testing, severity of patient symptoms, and response to neuromodulator drugs such as amitriptyline.

A discussion of the limitations of this study is warranted. A survey regarding a specialty-focused disorder such as CLPN is more likely to be completed by practicing laryngologists who are familiar with this disorder. In addition, our response rate could have been affected by lack of time to complete the survey, lack of incentive, or inaccurate contact information. We were also limited by the method of contact for each group, as both databases were composed mostly of email addresses. Even though each group received 3 emails approximately a month apart, a mixed survey may have been best. There have been previous reports indicating that Internet surveys have a lower response rate than mail-based surveys and that health care providers may prefer mail-based surveys to Internet surveys.^15,16 Still, this study provides valuable insight about the evaluation and treatment of patients with chronic laryngopharyngeal symptoms among European and American laryngologists.

In addition, the relatively low response rate also raises concerns about sampling bias, particularly in the ALA group. The members of this society are more likely to advocate for the concept of CLPN than their European counterparts. However, given the strong differences seen, this study highlights that there is a gap in familiarity for at least some portion of European laryngologists. Most important, this study indicates that a European presence in the investigation of this disorder could significantly add to the literature and advance the laryngology community as a whole.