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Abstract
Background and purpose Sudden sensorineural hearing loss (SSNHL) is a neurological and otolaryngological emergency during which rapid diagnosis and early treatment are of great importance. Clinical experience indicates that a considerable number of patients with SSNHL have concurrent right-to-left shunt (RLS). With limited reports, the association between SSNHL and RLS is yet unclear and there is a need for large observational studies to explore their latent relationship.
Methods and analysis This proposed study is a prospective, observational case–control study. A total of 194 eligible participants matched in age and sex will be divided equally into two groups: 97 patients with SSNHL included in the case group and 97 individuals without SSNHL in the control group. Medical evaluations, including clinical characteristics, laboratory examination, audiological examination and ultrasonography examination, will be performed in all subjects. The primary outcome of the study is the difference in RLS rates between the groups. Differences in patent foramen ovale rates and other measured variables will be further assessed. A conditional logistic regression as a correlation analysis will be used to evaluate the relationship between RLS and SSNHL.
Discussion This study may provide evidence on the correlation between RLS and SSNHL in order to enrich the aetiology of SSNHL.
Ethics and dissemination The study protocol has been approved by the Ethics Committee of Peking University Shenzhen Hospital. A written informed consent form will be signed and dated by the participants and the researchers before the study begins. The results will be disseminated in peer-reviewed publications.
Trial registration number ChiCTR2200064067.
- head & neck surgery
- neurology
- ultrasonography
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STRENGTHS AND LIMITATIONS OF THIS STUDY
With improvements in eligibility criteria and sample sizes, this study aims to reflect the relationship between right-to-left shunt (RLS) and sudden sensorineural hearing loss (SSNHL), which is rarely reported.
The major strength of the study will be the evaluation of patent foramen ovale rates in patients with SSNHL who were detected positively with an RLS.
This research is restricted to a single centre, with a non-prospective design and only with Chinese participants.
The causality of RLS and SSNHL remains unknown.
Background
Sudden sensorineural hearing loss (SSNHL) is an abrupt, unaccountable sensorineural hearing loss of over 30 dB across three contiguous pure-tone frequencies occurring within 72 hours, according to the 2019 definition of the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF).1 The global incidence of SSNHL is 5–27 per 100 000 people annually.1–3 Most patients suffer from a sudden unilateral hearing loss, while a few patients have bilateral deafness.1 4 Beginning with hearing loss, SSNHL may also lead to tinnitus, stuffy ears and dizziness.2 5 6
Commonly diagnosed in clinical practice, SSNHL is one of the neurological and otolaryngological emergencies. So far, several studies have found that the pathogenesis of SSNHL may be associated with multiple diseases, such as Meniere’s disease, acoustic schwannoma, intracranial demyelination,1 7 8 and haemorrhagic or ischaemic stroke.1 9 10
However, merely 10% may be diagnosed with a definite cause and the remaining 90% will always be diagnosed with unknown reasons.3 11 12 Moreover, mental stress, emotional pressure and irregular lifestyle may potentially act as inducing factors. Currently, the conventional treatments of SSNHL include corticosteroids, hyperbaric oxygen therapy and medications that may improve the microcirculation of the inner ear.1 However, the prognosis of SSNHL remains individually different, with a reported recovery rate of 30%–65%.13 14 Although favourable outcomes are believed to benefit from targeted and early interventions, uncertainty and diversity still exist in the prognosis of individual patients with SSNHL.
The precise aetiology of SSNHL has not been identified, but several pathophysiological mechanisms have been proposed. Atherosclerosis, hypertension, thrombophilia, vasospasm, hyperviscosity and paradoxical embolism have been investigated to correlate with SSNHL, but this requires harder pathological evidence.15 Of these mechanisms, vascular occlusion may be a common cause of the dysfunction. Supplied by an end artery, a vascular occlusion in the cochlea was proposed to be a cause of SSNHL early in 1949.15 16 Sudden hearing loss as an initial symptom that sometimes precedes stroke is usually seen in patients suffering from an acute ischaemia in the posterior circulation, particularly occlusion of the anterior inferior cerebellar artery (AICA).12 17 In addition to SSNHL, vertigo, nystagmus, facial weakness and gait ataxia are common symptoms. One of the most common aetiologies of occlusion leading to SSNHL is thromboembolism. Although the association between SSNHL and inherited thrombophilic risk factors lacks evidence, isolated studies have reported its correlation with hyperviscosity and paradoxical embolism. Contrast saline transcranial Doppler ultrasonography (c-TCD) can be used to screen patent foramen ovale (PFO) and pulmonary arteriovenous fistula.18 19 Ciorba et al reported a patient with SSNHL with right-to-left shunt (RLS) detected by c-TCD in whom PFO was further identified.20 A small study was undertaken to discover the association between RLS and SSNHL by matching patients with this disorder and controls.21 The study suggested a correlation between RLS and SSNHL; however, the mechanism remains undetermined. Therefore, we hypothesise that the positive rate of RLS in patients with SSNHL is higher than in individuals without SSNHL. We aim to use c-TCD as an imaging technique to investigate the characteristics of RLS and its correlation with SSNHL in the Chinese population.
Aim of this study
The study aims to explore the correlation between RLS and SSNHL by assessing the positive rates and characteristics of RLS between patients with SSNHL and normal people using c-TCD.
Study methods
An individual case–control study will be conducted at Peking University Shenzhen Hospital in China. The study protocol has been approved by the ethics committee and will follow standard recommendations (Strengthening the Reporting of Observational Studies in Epidemiology).
Subjects
Inclusion criteria
Case group
Patients included in this study need to be diagnosed with SSNHL by an otolaryngologist or neurologist based on the definition of 2019 AAO-HNSF: SSNHL is a sudden hearing loss of greater than 30 dB across three contiguous pure-tone frequencies occurring within 72 hours but unable to determine an exact cause.
Control group
The control group will include healthy individuals without hearing insufficiency.
Exclusion criteria
Subjects who met the following conditions will be excluded from this study:
Conductive hearing loss.
External ear inflammation, tympanitis, cholesteatoma of the middle ear or ear sclerosis.
Meniere’s disease.
Congenital hearing loss.
Vestibulocochlear benignant or malignant tumour.
Syphilitic deafness.
History of ear injury or trauma.
History of drug-induced hearing loss.
Serious heart and lung insufficiency.
Sample size
Sample size calculations were based on the formula for a case–control observational study. Previous studies have suggested that the positive rate of RLS was nearly 25% in the normal population and 50% in patients with SSNHL. With bilateral significance level α of 0.025 and β of 0.10 set, the sample size was estimated at 87 both in the case group and in the control group. Considering a 10% loss rate, 97 samples in each group are required.
Ratio of cases to controls
All subjects to be included are 18–65 years of age. The ratio of cases to controls will be 1:1. Matching of cases and controls will be principally based on age and sex. Finally, 97 patients with SSNHL and an equivalent number of normal people as controls will be enrolled in this study.
Patient and public involvement
Consent will be obtained directly from the participants. Patient enrolment will start on 1 January 2024 and the whole study is planned to last for 6 months.
Objectives
Subjects who meet the research requirements will receive a series of medical evaluations during the study after signing a written informed consent. Clinical data will be calculated and analysed to validate the hypothesis. An overview of our study design and the procedure is presented in figure 1.
Study flow chart. AAO-HNSF, American Academy of Otolaryngology-Head and Neck Surgery Foundation; c-TCD, contrast saline transcranial Doppler ultrasonography; PFO, patent foramen ovale; RLS, right-to-left shunt; SSNHL, sudden sensorineural hearing loss; TEE, transoesophageal echocardiography.
Primary outcome analyses: positive rates and characteristics of RLS
All participants are examined by c-TCD to detect the presence and the characteristics of RLS, which is monitored and defined by microembolic signals within 10 s on the screen during the examination.22 According to international consensus, the microembolic signals are defined as follows: (1) short duration <300 ms, (2) signal intensity ≥3 dB than the background signal, (3) unidirectional in the spectrum and (4) accompanied by sharp whistles. In addition, the size of the shunt will be categorised into three grades: grade 1: microembolic signals; grade 2: minor shunt, from 1 to 10 microbubbles screened at unilateral or bilateral middle cerebral arteries (MCA); grade 3: moderate shunt, more than 10 but without the curtain effect (refers to a shower of microembolic signals where a single signal cannot be identified); and grade 4: large shunt, more than 25 microbubbles with or without the curtain effect. After detection, the shunt will be classified into two types: (1) inherent type, shunts appearing immediately in a normal breathe and (2) latent type, shunts appearing in the Valsalva breathe, not a normal breathe.
Secondary outcome analyses: positive rates of PFO
Participants combined with an RLS as grade 2 or grade 3 will be further detected by transoesophageal echocardiography examination (TEE) to define whether they have a PFO.
The primary study hypothesis is that the positive rate of RLS in patients with SSNHL is higher than in the controls. In addition, the positive rates of PFO in the two groups are compared. Statistical analysis will be conducted mainly using Pearson χ2 test, followed by Fisher’s exact test as the post-hoc test if needed.
Clinical baseline characteristics
A questionnaire is designed by physicians trained professionally. All participants in the study will receive a semistructured questionnaire that includes basic information on age, sex, marriage, occupation, medical history and living habits. Medical history mainly includes information on whether they suffer from hypertension, diabetes and so on, while smoking and drinking are classified as living habits. Examples are listed in the following:
Hypertension: (1) systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg measured twice on different days; (2) diagnosed in the past; and (3) history of taking long-time oral antihypertensive medication. Subjects who are eligible with at least one of these conditions will be diagnosed with hypertension.
Diabetes: (1) fasting venous blood glucose ≥7.0 mmol/L or random venous blood glucose ≥11.1 mmol/L; (2) diagnosed in the past; and (3) history of taking long-time oral hypoglycaemic medication. Subjects who are eligible with at least one of these conditions will be diagnosed with diabetes.
Hyperlipidaemia: (1) total cholesterol ≥6.22 mmol/L or triglyceride ≥2.26 mmol/L or high-density lipoprotein ≤1.04 mmol/L or low-density lipoprotein ≥4.14 mmol/L; (2) diagnosed in the past; and (3) history of taking long-time oral medication. Subjects who are eligible with at least one of these conditions will be diagnosed with hyperlipidaemia.
Body mass index: weight (kg)/height (cm2).
Smoking: more than one cigarette a day lasting for more than half a year.
Drinking: alcohol intake at least once a week lasting for more than half a year.
Exercise: at least three times a week and 30 min or more each time.
Other potential variates to be collected: income, marital status, employment status, history of toxic exposure, family history, medication history and so on.
Medical examinations
Basic medical examinations include height, weight and vital signs. Blood routine examination, blood glucose, blood lipids, homocysteine, liver and kidney function, electrolytes, coagulation function, D-dimer and ECG will be performed in all participants as well.
Audiological examination
All participants will undergo a pure-tone audiogram from 250 Hz to 8000 Hz. Patients in the case group, who complained of hearing loss, should be admitted with a suitable otolaryngological examination within 30 days from the first onset of manifestations. Pure-tone average (PTA) will be calculated using an arithmetic mean of the hearing thresholds at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz in the affected ear. Hearing severity is classified into four degrees: I, mild: 25 dB≤PTA<40 dB; II, moderate: 41 dB≤PTA<60 dB; III, severe: 61 dB≤PTA<80 dB; IV, extremely severe: PTA ≥81 dB.
Ultrasonography examinations
During c-TCD examination, the MCA will be identified from the temporal window at a general depth of 50–55 mm by a 2×106 Hz handheld transducer (Delica EMS-9A TCD Detector, Shenzhen Delica Medical Equipment, China). A mixed solution of 9 mL saline and 1 mL air will agitate into bubble-containing saline between two 10 mL syringes. An indwelling catheter placed in the participant’s anterior cubital vein will connect the syringes with a three-way stopcock. The bubble-containing saline will be injected under two conditions: either no Valsalva manoeuvre or with Valsalva manoeuvre. Together with the injections being started, the monitoring of microembolic signals will be dynamically stored and determined whether there is a shunt and also its characteristics. If it is insufficient to detect MCA by the temporal bone windows, the occipital bone windows can be another choice. However, in order to ensure consistency of the detection method, we opted for temporal bone windows since there is no significant difference between the positive rates of vertebral artery and MCA monitoring for RLS detection.23
A specialist neurologist will perform c-TCD on the participants blindly. Participants in whom RLS is detected positively by c-TCD will be further examined by TEE to confirm whether the RLS is a PFO.
Quality control
Quality control was carried out during participant enrolment, questionnaire survey, medical examination, data entry and statistical analysis. A written protocol and standard operating procedures will be provided to all physicians and research assistants participating in the research. All of them should undergo standardised training and pass the assessment. Data from every participant will be collected and verified regularly by a researcher. Another researcher will be responsible for supervision.
Participants can withdraw from the study for any reason at any time. The clinician will ask if the participant is willing to complete the evaluation based on the current research schedule. The incidence of loss to follow-up and participant withdrawals will be recorded.
Statistical analysis
Descriptive analysis
By group of participants, the study population will be described using available data, mean, SD, median, minimum and maximum for quantitative variables. Qualitative variables will be expressed by absolute and relative frequencies (%).
Regression analysis
A conditional logistic regression model of multivariate analyses will be conducted to examine the association between RLS and SSNHL. The potential importance of differently measured variables will be further assessed by logistic regression.
Data are calculated using SPSS Statistics V.22.0. We consider statistical significance at a two-tailed p value of <0.05.
Ethical issues and dissemination
The study protocol has been approved by the Ethics Committee of Peking University Shenzhen Hospital. All understandable documents with related information in the preferred language will be provided by the investigators. Before the participants are accepted into the study, a written informed consent form will be signed and dated by both the participant and the investigator. The final findings will be disseminated in peer-reviewed publications.
Discussion
The aetiology and pathogenesis of SSNHL remain unclear, with vascular occlusion16 and viral infection24 the common causes. Current studies have found that auditory artery vasospasm, vascular embolism and thrombosis are the main vasogenic mechanisms.1 12 Originating from the basilar artery, the AICA runs along the pons and the middle foot of the cerebellum. The internal auditory artery is the end branch of AICA and supplies blood flow to the cochlea and vestibule.25 When thromboembolic blocks the specific arteries, sudden hearing loss or vertigo may occur.17 25 Prompt initiation such as angiography examination and thrombus assessment are recommendation for SSNHL to be distinguished from stroke.3 While several clinical reports have showed that patients suffering from sudden deafness with or without vertigo may combine with an RLS.
RLS refers to a potential abnormal channel between the systemic circulation and the pulmonary circulation. During the isovolumic systole or early ventricular diastole, the increasing pressure of the thoracic cavity leads to a high-pressure difference between the two atria or two ventricles, resulting in an RLS through the channel.26 RLS is usually divided into intracardiac and extracardiac, and PFO accounts for almost the largest proportion of the former. It is suggested that PFO occurs in 20%–30% of healthy adults, and the proportion is as high as nearly 50% in young patients with cryptogenic stroke.27 28 Mainly detected by transthoracic echocardiography, TEE or right ventricular catheterisation in clinical practice, PFO closure is nowadays considerably detected by c-TCD due to its reliable, non-invasive and accurate diagnostic value as part of the workup.29 A certain proportion of elderly patients with RLS have also been found,28 indicating that paradoxical embolism is a cause of stroke. Thromboembolic or vascular substances through RLS may lead to a paradoxical embolism of intracranial arteries instead of being filtrated and eliminated from the normal circulation. Research has indicated that SSNHL can probably predict the risk of ischaemic stroke and even a prodromal manifestation of it because they overlap in some risk factors.9 10 25 30 Therefore, paradoxical embolism may be a risk factor for SSNHL, which also reflects the potential risk for ischaemic stroke.
A recent observational study indicated that RLS was significantly associated with vestibular disease, especially benign recurrent vertigo and vestibular migraine.31 While the association between RLS and sudden deafness is rarely reported, two former case–control studies found that the positive rate of RLS in patients with SSNHL was nearly 50%.21 32 Iguchi et al21 presented a significantly higher proportion of patients with SSNHL than that of the normal population (48% vs 17%, p=0.011), indicating the correlation between RLS and SSNHL. RLS may be an identifiable cause of SSNHL. However, the studies had several limitations. The outcomes of this study may be affected by the small sample size and the differences in age and sex and other confounding factors between the SSNHL and the control group. Moreover, RLS in participants will be detected only by c-TCD without further examinations of its location.
We hope that the results of the current protocol can provide more convincing evidence that indicates the relationship between RLS and SSNHL, which could benefit the pathogenic diagnosis and treatment strategy for SSNHL.
Ethics statements
Patient consent for publication
References
Footnotes
Twitter @Jianrong Zheng
Contributors Study concept and design were fulfilled by JZ, WY and JH. JZ wrote the manuscript, which was modified by WY and JH. YZ, YC, CL and BL performed the statistical analysis. All authors revised the content and approved the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; externally peer reviewed.