So Young Kim, MD, PhD; Chang Ho Lee, MD, PhD; Dae Myoung Yoo, MS; Mi Jung Kwon, MD, PhD; Ji Hee Kim, MD, PhD; Joo-Hee Kim, MD, PhD; Bumjung Park, MD, PhD; Hyo-Jeong Lee, MD, PhD; Hyo Geun Choi, MD, PhD, *Ayman Ahmed Rabe Hussein Helal, *Department of health DOH -Abu Dhabi, UAE

Author Affiliations:

Department of Otorhinolaryngology–Head & Neck Surgery, CHA Bundang Medical Center, CHA University, Seongnam, Korea (S. Y. Kim, C. H. Lee); Hallym Data Science Laboratory, Hallym University College of Medicine, Anyang, Korea (Yoo, Choi); Department of Pathology, Hallym University College of Medicine, Anyang, Gyeonggi-do, Korea (Kwon); Department of Neurosurgery, Hallym University College of Medicine, Anyang, Gyeonggi-do, Korea

(J. H. Kim); Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Hallym University College of Medicine, Anyang, Gyeonggi-do, Korea (J.-H. Kim); Department of Otorhinolaryngology–Head & Neck Surgery, Hallym University College of Medicine, Anyang, Korea (Park, H.-J. Lee, Choi).

Corresponding Author:

Hyo Geun Choi, MD, PhD, Department of Otorhinolaryngology–Head & Neck Surgery, Hallym University Sacred Heart Hospital, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do 14068, Republic of Korea (pupen@naver.com).

 

ConferenceMinds Journal: This article was published and presented in the ConferenceMinds conference held on 27th Sep 2023 | London, UK.

PSIN : 0003376267 / HHW5289D/ 369H/ 2023 / 82HS532N / SEP 2023

Importance:

A connection between Meniere disease (MD) and migraine has been proposed, but the temporal association remains unknown.

Objective:

To examine the bidirectional association of MD with migraine.

Design, Setting, and Participants:

This case-control study included participants 40 years or older from the Korean National Health Insurance Service Health Screening Cohort from 2002 to 2015.

Main Outcomes and Measures:

A total of 6919 patients with MD were matched with 27 676 control participants without MD for age, sex, income, region of residence, and index date.

The incidence of migraine was analyzed in the MD and matched groups using a stratified Cox proportional hazard regression model. In addition, 35 889 patients with migraine were matched with 71 778 control participants without migraine. The incidence of MD was analyzed using a stratified Cox proportional hazard regression model.

Results: 

Of 142 262 total participants, 94 611 (66.5%) were women. Migraine occurred in 695

of 6919 patients with MD (10.0%) and 970 of 27 676 matched control participants (3.5%). The MD group demonstrated a 2.22-fold higher risk of migraine than the matched control group (95% CI, 1.99-2.49). Meniere disease was present in 1098 of 35 889 patients with

migraine (3.1%) and 781 of 71 778 matched control participants (1.1%). The migraine group had a 1.95-fold higher risk of MD than the matched control group (95% CI, 1.77-2.15).

Conclusion and Relevance: 

The results of this case-control study suggest that patients with MD had a greater risk of migraine occurrence. Furthermore, patients with migraine had a higher risk of MD. Based on the bidirectional association, therapeutics for migraine could potentially be applied to MD and vice versa.

Meniere disease (MD) is a clinical diagnosis with a spec- trum of audiovestibular symptoms. The prevalence of MD is presumed to be approximately 50 to 200 per 100 000 adults. Meniere disease is more common in women and those aged 40 to 60 years. Although the precise etiology of MD cannot be confined to a single pathophysiology, endolymphatic hydrops has been considered one of the common pathophysiologies of MD. Endolymphatic hydrops and subsequent damage to the inner ear can have multiple causes, such as infectious, immunologic, metabolic, vascular, and traumatic causes. Migraine is a clinical disease with a primary headache with or without accompanying aural symptoms of visual, movement, and sensory systems. The global prevalence of migraine was estimated to be approximately 14.1%. The occurrence of migraine is higher in the female population and increased among individuals age 40 to 44 years. The pathophysiology of migraine is complex and mainly involves the trigeminovascular system. The trigeminal Meniere disease and migraine are frequently simultane- ously occurring diseases. In addition, MD and migraine share the pathophysiology of immune and vascular compromise and innervation of the trigeminal nerve in the labyrinthine artery.  Thus, we hypothesized that MD and migraine may have a reciprocal association. To examine this assumption, 2 independent longitudinal follow-up studies were planned in a nationwide health screening cohort. First, the occurrence of migraine was investigated in patients with MD and matched participants without MD. Second, the development of MD in patients with migraine was analyzed in patients with migraine and matched participants without migraine.

Key Points

Question What is the temporal association between Meniere disease (MD) and migraine?

Findings In this case-control study of 6919 patients with MD and 27 676 controls, MD and migraine demonstrated bidirectional associations. Patients with MD had a higher risk of developing migraine, and patients with migraine had an increased risk of MD.

Meaning The study results suggest that clinical management of MD can be improved by considering the possible comorbidity of migraine. Novel therapeutic agents could be developed based on the reciprocal association between the 2 diseases.

Methods

Ethics

The present study was approved by the ethics committee of Hallym University. The institutional review board waived the requirement of written informed consent. This study conformed to the guidelines of the ethics committee of Hallym University.

Study Population and Participant Selection

In this study, Korean National Health Insurance Service- Health Screening Cohort data were analyzed. Participants with MD were chosen from 514 866 participants with 615 488 428 medical claim codes from 2002 through 2015 (n = 9032). The matched control group was enrolled if participants were not defined as having MD during the total study period (n = 505 834). To select participants who received a diagnosis of MD for the first time during the follow-up period, participants with MD diagnosed in 2002 were disqualified from the MD group (washout period; n = 476). One participant with MD was excluded owing to missing data for the total cholesterol level. The participants who received a diagnosis of MD at 1 point or had missing pure tone audiometry data were excluded from the matched group (n = 16 586). The participants with histories of head trauma (n = 289 for MD, n = 12 613 for matched), brain tumors (n = 15 for MD, n = 825 for matched), disorders of acoustic nerves (n = 23 for MD, n = 120 for matched), or benign neoplasms of cranial nerves (n = 25 for MD, n = 191 for matched) were disqualified. Age, sex, income, and region of residence were matched between participants with MD and matched control participants. The matched control participants were sorted using a random number order. The index date was defined as the date of diagnosis of MD and the enrollment date of matched control participants with MD. The participants who died before the index date were excluded from the matched group. To exclude participants with previous histories of migraine and include only participants with migraine newly diagnosed during the follow-up period, participants with a history of migraine were not enrolled in either the MD or matched control group. In the MD group, 1284 participants were disqualified. During the matching procedure, 447 823 matched control participants were excluded. Finally, 6919 participants with MD and 27 676 matched control participants were enrolled (Figure, A).

Participants with migraine were newly selected from the whole cohort population (n = 44 395). The matched control group was enrolled and did not have a history of migraine during the follow-up period (n = 470 471). To select participants who received a diagnosis of migraine for the first time during the follow-up period, participants with migraine diagnosed in 2002 were excluded (washout period; n = 6230). Participants with migraine for whom body mass index (calculated as weight in kilograms divided by height in meters squared), fasting blood glucose level, or total cholesterol level data were missing were excluded (n = 8). The participants who had a history of migraine were excluded from the matched control group (n = 44 875). Participants who had histories of head trauma (n = 1393 for migraine, n = 10 518 for matched), brain tumors (n = 86 for migraine, n = 697 for matched), disorders of acoustic nerves (n = 25 for migraine, n = 110 for matched), or benign neoplasms of cranial nerves (n = 31 for migraine, n = 173 for matched) were disqualified. Age, sex, income, and region of residence were matched between participants with migraine and matched control participants. To exclude the participants with previous histories of MD and include only participants with MD that was newly diagnosed during the follow-up period, participants who received a diagnosis of MD before the index date were excluded from the migraine and matched groups (n = 733 in the migraine group). Finally, 35 889 participants with migraine and 71 778 matched control participants were enrolled (Figure, B).

Patients with MD

Meniere disease was defined based on the H810 diagnostic code (International Statistical Classification of Diseases and Re- lated Health Problems, Tenth Revision [ICD-10]) (MD). We se- lected the participants who visited clinics 2 or more times and underwent pure tone audiometry.

Patients with Migraine

Patients with migraine were considered those who received a diagnosis with the ICD-10 code G43 2 or more times during the follow-up period.24 Migraines were specified as migraines with aura and migraines without aura (G431).

A, In total, 6919 participants with Meniere disease (MD) and 27 676 matched control participants were enrolled. B, In total, 35 889 participants with migraine and 71 778 matched control participants were enrolled. Analyses using stratified Cox proportional hazard regression model. Adjustment: age, sex, income,

Covariates
Age groups were classified based on 5-year intervals. Five income groups were specified based on the health claim data. Urban and rural regions of residence were classified based on the administrative region.

Tobacco smoking, alcohol consumption, obesity, systolic blood pressure, diastolic blood pressure, fasting blood glucose level, and total cholesterol level were surveyed and measured. The comorbidities were scored from 0 through 29 based on the Charlson Comorbidity Index. The histories of benign paroxysmal vertigo (ICD-10 code: H811), vestibular neu- ronitis (ICD-10 code: H812), and other peripheral vertigo (ICD-10 code: H813) were designated if the participants had histories of being treated 2 or more times.

Statistical Analyses

The difference in proportion with 95% CIs was calculated to estimate the effect size between 2 groups.25 Because a tiny difference in large study population can result in statistically significant P values, this study calculated difference to measure the equivalence of variables between 2 groups.

A stratified Cox proportional hazards model was applied to analyze the hazard ratio (HR) of MD for migraine and the HR of migraine for MD. Crude (simple) and adjusted (obesity, smoking, alcohol consumption, systolic blood pressure, diastolic blood pressure, fasting blood glucose level, total cholesterol level, Charlson Comorbidity Index scores, benign paroxysmal positional vertigo [BPPV], vestibular neuronitis, and other peripheral vertigo) models were applied with the 95% CIs. Age, sex, income, and region of residence were stratified. Kaplan-Meier curve analysis and log rank tests were conducted. The E value was evaluated to assume the effects of unconsidered confounders.26-29 An E value higher than the association of unconsidered possible confounders with the exposure/outcome indicated a valid association between MD and migraine in this study.

Subgroup analyses were conducted according to age, sex, income, and region of residence. For unmatched variables, an unstratified Cox proportional hazards model was applied in subgroup analyses.

Two-tailed analyses were conducted, and P < .05 was considered a significant difference. Analyses were performed with SAS, version 9.4 (SAS Institute).

Results

In the total population (514 866 participants), 44 395 participants (8.6%) had histories of migraine. Among these patients with migraine, 2233 of 44 395 (5.0%) had histories of MD. Conversely, 9032 participants (1.8%) had histories of MD. Among these patients with MD, 2233 of 9032 (24.7%) had histories of migraine.

A total of 695 of 6919 (10.0%) and 970 of 27 676 (3.5%) of the MD and matched control groups, respectively, had histories of migraine (Table 1; eTable 1 in the Supplement). Migraines with and without aura were more common in the MD group than in the matched control group. The prevalence rates of BPPV (32.3% vs 5.6%), vestibular neuronitis (10.3% vs 1.3%), and other peripheral vertigos (21.9% vs 4.1%) were greater in the MD group than in the matched control group. Thus, all these covariates were adjusted in the adjusted models.

In the migraine and matched control groups, 1098 of 35 889 (3.1%) and 781 of 71 778 (1.1%), respectively, had histories of MD (Table 1; eTable 1 in the Supplement). The BPPV (13.7% vs 5.6%), vestibular neuronitis (3.7% vs 1.3%), and other peripheral vertigo (10.4% vs 4.0%) were distinct between the migraine and matched control groups. The E value of MD for migraine (HR, 3.87; 95% CI, 3.39-4.42) was higher than that in previous studies that reported factors associated with migraine, including depression, anxiety, and stress (odds ratio, 2.1-3.5).

The follow-up duration was 32 480 person-years for the MD group and 136 594 person-years for the matched control group (Table 2). The incidence rate of migraine was 214 person- years for the MD group and 71 person-years for the matched control group. Meniere disease was associated with a 2.22- fold greater HR for migraine (95% CI, 1.99-2.49) (Table 2) and with 2.00-fold (95% CI, 1.36-3.05) and 2.23-fold (95% CI, 1.98-

2.50) higher HRs for migraine with and without aura, respectively. The E value of migraine for MD was as high as 3.31 (95% CI, 2.94-3.72), which is higher than previously reported associated factors of MD not considered in the present study, including immune dysfunction, autonomic dysfunction, and poor mental health (odds ratio, 1.5-2.2).33 The higher HR of MD for migraine was valid in many subgroups (eTables 2 and 3 in the Supplement).

The follow-up duration was 245 196 person-years for the migraine group and 489 986 person-years for the matched control group (Table 3). The incidence rate of MD was 44.8 person- years for the migraine group and 15.9 person-years for the matched control group. Migraine was associated with a 1.95- fold higher HR for MD (95% CI, 1.77-2.15) (Table 3). Migraine with and without aura were associated with 2.13-fold (95% CI, 1.49-3.03) and 1.93-fold (95% CI, 1.75-2.13) greater HRs for MD (both P < .001), respectively. The higher HR of migraine for MD was consistent in many subgroups (eTables 4 and 5 in the Supplement).

Discussion

In this case-control study, the occurrence of MD was higher in patients with migraine. Moreover, the occurrence of migraine was higher in patients with MD. The bidirectional association of MD and migraine was valid for migraines with aura and without aura. Several previous studies have suggested an association between MD and migraine.21,34,35 However, to our knowledge, few studies have demonstrated the bidirectional association of these diseases.

Moreover, this study adjusted for demographic characteristics, lifestyle, and comorbidities, including other vestibular diseases. Although there could have been other confounders, the E values of the current study were higher than those of previously reported associated factors. This suggests that the associations of MD with migraine and migraine with MD observed in the present study are valid even if the analysis also adjusts for these unconsidered potential confounders.

Several plausible mechanisms, including neurovascular crosstalk and channelopathies, can mediate the association of migraine with MD. The vestibular system and trigeminal nervous system are connected via neurovascular branches, which can mediate the association of MD with migraine. The vestibular-cochlear branch of the trigeminal nerve sup- plies the vasculature of the vestibule and cochleae. Thus, the dysregulated trigeminal nerve activities associated with migraine could affect vestibulocochlear function via neurovascular connections. It has been suggested that migraine is associated with inner ear injuries.11,38 Patients with migraine manifest abnormal activation of the trigeminal nervous system, releasing neurotransmitters with vaso- dilation actions.39 Through the ophthalmic branch of the trigeminal nerve, the labyrinth artery could be affected by these vasodilators, which results in cochleavestibular dysfunctions. For instance, a case report with autopsy findings of a patient with long-standing migraine demonstrated ischemic insult in the cochlea because of a migraine- associated vasospasm. Moreover, channelopathies in migraine can increase the susceptibility of patients with migraine to develop MD.40 It has been reported that brain calcium channel dysfunction is associated with migraine and episodic vertigo as a result of the increased extracellular potassium level, which induces the spread of depression in migraine and endolymphatic hydrops of the inner ear.

However, there are some possible mediators of the association of MD with migraine. First, chronic inflammatory conditions in MD could stimulate the trigeminal nervous system in the inner ear, thereby inducing migraine. Several inflammatory pathways, such as nuclear factor κ B and tumor necrosis factor signaling, can be involved in the development of MDs. These inflammatory pathways were also reported to be activated in preclinical studies of migraine. Thus, the chronic activation of neuro inflammation can link the association of MDs with migraine. Second, the chronic hydropic inner ear may be vulnerable to migrainous attack because of the impaired autoregulation of endolymphatic flow. Third, MD can elevate the susceptibility to migraine as a result of stress and other psychological distress in patients with MD. Fourth, other common triggering factors of migraine and MD, including weather and dietary factors, could be linked with the association of the 2 diseases.

The bidirectional associations between MD and migraine were valid in all subgroups. In contrast, a cross- sectional study examined the specific features of patients with MD combined with migraine. There was a greater rate of migraine in female patients with MD, clinical manifestations of frequent vertigo attacks, better hearing levels, and specific anatomical features.13 The large study population could potentiate the reciprocal association between MD and migraine in subgroups of this study. Although a significant association between MD and migraine was observed in all subgroups, the middle-aged, male, and comorbid conditions of hyperglycosemia and hypercholesterolemia sub- groups showed a stronger association between the 2 dis- eases in this study. The prevalent occurrence of these 2 diseases in the middle-aged group and the common patho-physiology of vascular compromise may potentiate the reciprocal associations of the 2 diseases in these subgroups. In addition, our results suggested that migraine with and without aura was associated with MD.

Strengths and Limitations

This study used a large study population that permitted matching and adjustment for numerous potential cofounders. Demographic factors, socioeconomic factors, life- style factors, and comorbidities were considered. In addition, other vestibular disorders were adjusted when analyzing the association between MD and migraine. However, because of the lack of information in health claim databases, the results of vestibular function tests and the degree of hearing loss could not be assessed. The overlap- ping recurrent vestibular symptoms among various disorders could confuse the diagnostic accuracy of MD. To attenuate the potential misdiagnosis, this study based the presence of the disease on diagnoses by physicians and 2 or more times of being treated. In Korea, MD was diagnosed in approximately 7.2% of patients with dizziness, which was similar to the findings in other countries. The etiologic factors were heterogeneous for MD and migraine. Moreover, the severity of diseases and treatment options could not be classified. Last, although many covariates were considered, there may have remained potential confounders, such as emotional distress. These limitations can be addressed by studying specific types of MD and migraine. The bidirectional association between migraine and MD also supports drug redistribution studies of the use of therapeutics for migraine in patients with MD possibly combined with migraine.

Conclusions:

In this case-control study of a nationally representative cohort of Korean adults, MD and migraine had bidirectional associations. Patients with MD showed a higher occurrence of migraine and vice versa. The diagnosis of migraine should be considered when patients with MD experience headache. Thus, the medicines for migraine could be effective in controlling symptoms of MD.

Article Information:

Accepted for Publication: February 17, 2022.

Published Online: April 7, 2022. doi:10.1001/jamaoto.2022.0331

Author Contributions: Dr Choi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Joo-Hee Kim, Park, H. Lee, Choi.

Acquisition, analysis, or interpretation of data: S. Kim, C. Lee, Yoo, Kwon, Ji Hee Kim, H. Lee, Choi. Drafting of the manuscript: S. Kim, Yoo, Joo-Hee Kim, Choi.

Critical revision of the manuscript for important intellectual content: S. Kim, C. Lee, Kwon, Ji Hee Kim, Park, H. Lee, Choi.

Statistical analysis: Yoo, Choi.

Obtained funding: Kwon, Choi.

Administrative, technical, or material support: Ji Hee Kim, H. Lee, Choi.

Supervision: S. Kim, C. Lee, Ji Hee Kim, Joo-Hee Kim, Park, H. Lee, Choi.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported in part by research grants (NRF-2018-R1D1A1A0-2085328; NRF-2021-R1C1C1004986) from the National Research Foundation (NRF) of Korea.

Role of the Funder/Sponsor: The NRF had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The manuscript was edited for proper English language, grammar, punctuation, spelling, and overall style by the native English-speaking editors at American Journal Experts, who were compensated for their contributions.

REFERENCES

  1. Frejo L, Martin-Sanz E, Teggi R, et al; Meniere’s disease Consortium. Extended phenotype and clinical subgroups in unilateral Meniere disease: a cross-sectional study with cluster analysis. Clin Otolaryngol. 2017;42(6):1172-1180. doi:10.1111/coa. 12844
  2. Basura GJ, Adams ME, Monfared A, et al. Clinical practice guideline: Ménière’s disease. Otolaryngol Head Neck Surg. 2020;162(2_suppl):S1-S55. doi:10. 1177/0194599820909438
  3. Watanabe Y, Mizukoshi K, Shojaku H, Watanabe I, Hinoki M, Kitahara M. Epidemiological and clinical characteristics of Menière’s disease in Japan. Acta Otolaryngol Suppl. 1995;519:206-210. doi:10.3109/ 00016489509121906
  4. Liu Y, Yang J, Duan M. Current status on researches of Meniere’s disease: a review. Acta Otolaryngol. 2020;140(10):808-812. doi:10.1080/
    00016489.2020.1776385
  5. Lee KS, Kimura RS. Ischemia of the endolymphatic sac. Acta Otolaryngol. 1992;112(4): 658-666. doi:10.3109/00016489209137456
  6. Derebery MJ. Allergic and immunologic aspects of Meniere’s disease. Otolaryngol Head Neck Surg. 1996;114(3):360-365. doi:10.1016/S0194-5998(96)
    70204-8
  7. Ferster APO, Cureoglu S, Keskin N, Paparella MM, Isildak H. Secondary Endolymphatic Hydrops. Otol Neurotol. 2017;38(5):774-779. doi:10.1097/ MAO.0000000000001377
  8. Mitka M. Experts sort out headache classification, new guidelines for physicians to debut. JAMA. 2003;290(6):736-739. doi:10.1001/ jama.290.6.736
  9. Tinsley A, Rothrock JF. What are we missing in the diagnostic criteria for migraine? Curr Pain Headache Rep. 2018;22(12):84. doi:10.1007/s11916- 018-0733-1
  10. Safiri S, Pourfathi H, Eagan A, et al. Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019. Pain. 2022; 163(2):e293-e309. doi:10.1097/j.pain. 0000000000002275
  11. Ma X, Ke YJ, Jing YY, Diao TX, Yu LS. Migraine and cochlear symptoms. Curr Med Sci. 2021;41(4): 649-653. doi:10.1007/s11596-021-2410-6
  12. Lempert T, Olesen J, Furman J, et al. Vestibular migraine: diagnostic criteria. J Vestib Res. 2012;22 (4):167-172. doi:10.3233/VES-2012-0453
  13. Diao T, Han L, Jing Y, et al. The clinical characteristics and anatomical variations in patients with intractable unilateral Meniere’s Disease with and without migraine. J Vestib Res. 2022;32(1):57-67. doi:10.3233/VES-190755
  14. Radtke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Neuhauser H. Migraine and Ménière’s disease: is there a link? Neurology. 2002; 59(11):1700-1704. doi:10.1212/01.WNL.0000036903.
    22461.39
  15. Parker W. Menière’s disease: etiologic considerations. Arch Otolaryngol Head Neck Surg. 1995;121(4):377-382. doi:10.1001/archotol.1995.
    01890040005001
  16. Ibekwe TS, Fasunla JA, Ibekwe PU, Obasikene GC, Onakoya PA, Nwaorgu OG. Migraine and Meniere’s disease: two different phenomena with frequently observed concomitant occurrences.
    J Natl Med Assoc. 2008;100(3):334-338. doi:10. 1016/S0027-9684(15)31246-3
  17. Meniere P. Pathologic auriculaire: menoires sur une lesion de l’oreille interne donnant lieu a des symptoms de congestion cerebrale apoplectiformes. Gaz Med Paris. 1861;16:597-601.
  18. Ghavami Y, Mahboubi H, Yau AY, Maducdoc M, Djalilian HR. Migraine features in patients with Meniere’s disease. Laryngoscope. 2016;126(1):163-
    168. doi:10.1002/lary.25344
  19. Espinosa-Sanchez JM, Lopez-Escamez JA. Menière’s disease. Handb Clin Neurol. 2016;137:257-277. doi:10.1016/B978-0-444-63437-5.00019-4
  20. Vass Z, Shore SE, Nuttall AL, Miller JM. Direct evidence of trigeminal innervation of the cochlear blood vessels. Neuroscience. 1998;84(2):559-567. doi:10.1016/S0306-4522(97)00503-4
  21. Sarna B, Abouzari M, Lin HW, Djalilian HR.
    A hypothetical proposal for association between migraine and Meniere’s disease. Med Hypotheses. 2020;134:109430. doi:10.1016/j.mehy.2019.109430
  22. Kim SY, Min C, Yoo DM, et al. Hearing impairment increases economic inequality. Clin Exp Otorhinolaryngol. 2021;14(3):278-286. doi:10. 21053/ceo.2021.00325
  23. Kim SY, Song YS, Wee JH, Min C, Yoo DM, Choi HG. Association between Ménière’s disease and thyroid diseases: a nested case-control study. Sci Rep. 2020;10(1):18224. doi:10.1038/s41598-020-
    75404-y
  24. Kim SY, Min C, Oh DJ, Lim JS, Choi HG. Bidirectional association between asthma and migraines in adults: two longitudinal follow-up studies. Sci Rep. 2019;9(1):18343. doi:10.1038/ s41598-019-54972-8
  25. Dalton DYaJE. A unified approach to measuring the effect size between two groups using SAS. SAS Global Forum 2012; April 22, 2012; Orlando, Florida.
  26. Haneuse S, VanderWeele TJ, Arterburn D. Using the e-value to assess the potential effect of unmeasured confounding in observational studies.
    JAMA. 2019;321(6):602-603. doi:10.1001/jama.2018.
    21554
  27. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the e-value. Ann Intern Med. 2017;167(4):268-274. doi:10.7326/ M16-2607
  28. Localio AR, Stack CB, Griswold ME. Sensitivity analysis for unmeasured confounding: e-values for observational studies. Ann Intern Med. 2017;167(4): 285-286. doi:10.7326/M17-1485
  29. Ding P, VanderWeele TJ. Sensitivity analysis without assumptions. Epidemiology. 2016;27(3): 368-377. doi:10.1097/EDE.0000000000000457
  30. Mäki K, Vahtera J, Virtanen M, Elovainio M, Keltikangas-Järvinen L, Kivimäki M. Work stress and new-onset migraine in a female employee population. Cephalalgia. 2008;28(1):18-25. doi:10. 1111/j.1468-2982.2007.01462.x
  31. Ulrich V, Olesen J, Gervil M, Russell MB. Possible risk factors and precipitants for migraine with aura in discordant twin-pairs: a population-based study. Cephalalgia. 2000;20(9):821-825. doi:10.1046/j. 1468-2982.2000.00135.x
  32. Roy R, Sánchez-Rodríguez E, Galán S, et al. Factors associated with migraine in the general population of Spain: results from the European Health Survey 2014. Pain Med. 2019;20(3):555-563. doi:10.1093/pm/pny093
  33. Tyrrell JS, Whinney DJ, Ukoumunne OC, Fleming LE, Osborne NJ. Prevalence, associated factors, and comorbid conditions for Ménière’s disease. Ear Hear. 2014;35(4):e162-e169. doi:10. 1097/AUD.0000000000000041
  34. Pyykkö I, Manchaiah V, Färkkilä M, Kentala E, Zou J. Association between Ménière’s disease and vestibular migraine. Auris Nasus Larynx. 2019;46 (5):724-733. doi:10.1016/j.anl.2019.02.002
  35. Pyykkö I, Pyykkö N, Manchaiah V. Vestibular drop attacks in Ménière’s disease and its association with migraine. Eur Arch Otorhinolaryngol. 2020; 277(7):1907-1916. doi:10.1007/s00405-020-05890-3
  36. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P. Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol. 2009;8(7):679-690. doi:10.1016/S1474-4422(09)70090-0
  37. Goadsby PJ, Charbit AR, Andreou AP, Akerman S, Holland PR. Neurobiology of migraine. Neuroscience. 2009;161(2):327-341. doi:10.1016/j. neuroscience.2009.03.019
  38. Lee H, Lopez I, Ishiyama A, Baloh RW. Can migraine damage the inner ear? Arch Neurol. 2000; 57(11):1631-1634. doi:10.1001/archneur.57.11.1631
  39. von Brevern M, Lempert T. Vestibular migraine. Handb Clin Neurol. 2016;137:301-316. doi:10.1016/ B978-0-444-63437-5.00022-4
  40. Baloh RW. Neurotology of migraine. Headache. 1997;37(10):615-621. doi:10.1046/j.1526-4610.1997. 3710615.x
  41. Frejo L, Requena T, Okawa S, et al. Regulation of Fn14 receptor and NF-κB underlies inflammation in Meniere’s disease. Front Immunol. 2017;8:1739. doi:10.3389/fimmu.2017.01739
  42. Edvinsson L, Haanes KA, Warfvinge K. Does inflammation have a role in migraine? Nat Rev Neurol. 2019;15(8):483-490. doi:10.1038/s41582-019-0216-y
  43. May A, Schulte LH. Chronic migraine: risk factors, mechanisms and treatment. Nat Rev Neurol. 2016;12(8):455-464. doi:10.1038/nrneurol.2016.93
  44. Yeo NL, White MP, Ronan N, Whinney DJ, Curnow A, Tyrrell J. Stress and unusual events exacerbate symptoms in Menière’s disease: a longitudinal study. Otol Neurotol. 2018;39(1):73- 81. doi:10.1097/MAO.0000000000001592
  45. Dlugaiczyk J, Lempert T, Lopez-Escamez JA, Teggi R, von Brevern M, Bisdorff A. Recurrent vestibular symptoms not otherwise specified: clinical characteristics compared with vestibular migraine and Menière’s disease. Front Neurol. 2021; 12:674092. doi:10.3389/fneur.2021.674092 region of residence, obesity, smoking, alcohol consumption, systolic blood pressure, diastolic blood pressure, fasting blood glucose level, total cholesterol level, benign paroxysmal vertigo, vestibular neuronitis, other peripheral vertigo, and Charlson Comorbidity Index scores.