The clinical characteristics and anatomical variations in patients with intractable unilateral Meniere’s disease with and without migraine

Abstract

BACKGROUND:

Migraine is more common in Meniere’s disease patients, who have some certain anatomical variations. But there are limited studies focusing on the anatomical variations in patients with Meniere’s disease and migraine.

OBJECTIVE:

To explore the clinical and anatomical features in Meniere’s disease patients with and without migraine, determining whether the coexistence of migraine can be used as a basis for clinical subtyping of Meniere’s disease.

METHODS:

Ninety-five Meniere’s disease patients and ninety-five healthy subjects matched with age, sex were selected. A detailed questionnaire based on the diagnosis criteria of Meniere’s disease and migraine was designed. According to the CT scan, we divided the mastoid cell system of all the subjects into two types: well-pneumatization type and poor-pneumatization type. Meanwhile, the shortest distance between the sigmoid sinus and the posterior wall of the external acoustic canal was measured.

RESULTS:

Compared with those without migraine, Meniere‘s disease patients with migraine had a higher female comorbidity, poorer mastoid pneumatization, shorter distance between the sigmoid sinus and posterior wall of the external acoustic canal, longer history, higher frequency of vertigo attacks and better average hearing threshold.

CONCLUSIONS:

In our study, anatomical features as well as several clinical manifestations were proved to differ significantly between Meniere’s disease patients with and without migraine, indicating the coexistence of migraine may be one standard for the clinical subtyping of Meniere’s disease.

Keywords

Meniere’s disease anatomical features clinical manifestations migraine subtype

1 Introduction

Meniere’s disease (MD) is considered as a heterogeneous disorder, characterized by vertigo, sensorineural hearing loss, tinnitus, and aural pressure. Several comorbidities, such as migraine and autoimmune disorder, have been associated with MD [13]. It has been suggested that migraine is more common in patients with MD [23]. There is a significant overlap between symptoms of this two conditions, which may share common pathophysiological mechanisms [25, 26], and the medications intended for migraine might be effective to manage MD patients [14]. In contrast, in 2007, a study of Y.H. CHA found that the patients with MD and migraine had an lower onset age of episodic vertigo or fluctuating hearing loss, and were more prone to have bilateral aural symptoms and hearing loss compared with patients with MD alone [7]. Our previous study also found that Meniere disease patients with and without migraine had differences in clinical features and vascular characteristics [32].

At present, the current diagnostic criteria of MD still depends mainly on clinical symptoms, lack of laboratory standards. As we know, the clinical manifestations of MD are heterogeneous, the diagnostic criteria cannot conduct the follow-up specific treatments. Therefore, some scholars have proposed the concept of clinical typing for MD [24]. In 2017, L. Frejo suggested that unilateral MD can be divided into 5 subgroups. Among them, group 4 is combined with migraine, namely whether with migraine accompanied could be used as a diagnostic basis for the clinical classification of MD [13].

As for the physiology of MD, the exact mechanism remains unclear. The most important histopathologic feature of MD is thought to be endolymphatic hydrops, which is related to multiple factors, including genetic, immunologic, infectious, metabolic, vascular causes and some anatomical variations, such as pneumatization of mastoid and anterior displacement of sigmoid sinus (ADSS) [22]. Numerous studies have been conducted on the relationship between the degree of mastoid pneumatization and MD. Jan Stahle reported in 1983 that there was a reduction in size and a lack of pneumatization of the mastoid air cell system in MD patients [29]. The correlation between anteriorly-displaced sigmoid sinus and MD has also been demonstrated in previous studies. The study by Michael M has proposed that anteriorly-displaced sigmoid sinus might lead to the occurrence of MD [22]. But, there are limited studies focusing on the anatomical variations in patients with MD and migraine. In 2019, David Bachinger suggested that MD can be divided into two types according to the degree of the vestibular aqueduct development, and the incidence of migraine during group with vestibular aqueduct dysplasia is significantly increased [6]. That is to say, patients with MD and migraine may have some certain anatomical features.

In this study, 95 randomly selected MD patients were divided into two groups according to whether with migraine accompanied or not. The clinical and anatomical features were analyzed and compared to explore whether there are some characteristic clinical and anatomical features in MD patients with migraine, providing a theoretical basis for the clinical classification and follow-up treatment of MD.

2 Materials and methods

2.1 Study design

This is a retrospective, observational clinical study. In this study, patients with clinically diagnosed MD and healthy controls with matched age and sex were selected as subjects. First, we compared the anatomical variations between MD patients and the healthy controls. Then, we divided all the patients with MD into two groups according to whether or not with migraine accompanied, and compared the clinical manifestations and anatomical features to provide the theoretical basis for the clinical classification of MD patients.

2.2 Patients

All adult patients aged between 20 to 80 years old, who presented to the Otolaryngologic Department in Peking University People’s Hospital from 1 Jan 2015 to 1 Jan 2017 with a complaint about spontaneous episodes of vertigo within the past several years, were asked to fill in a questionnaire. There were 110 patients initially diagnosed with unilateral definite MD based on the diagnostic criteria in 2015 [17], among which 95 patients were included in the final analysis and 15 patients were excluded based on the exclusion criteria. The control group consisted of 95 randomly selected patients who were hospitalized for surgery due to deviated nasal septum during the same period, matched with age, without history including vertigo attacks and hearing loss, and also never being diagnosed with migraine, MD or any other middle ear diseases. All the cases were selected by stratified sampling method. This study identified 10-year-olds as a group, then stratified and sampled at a ratio of 1:1 in the same age group of the control group. All the Meniere disease’s patients were then divided into two groups according to whether they were accompanied by migraine based on the third edition of the International Classification of Headache Disorders(ICHD-III) criteria for migraine [1].

Patients were excluded if they had: 1) acoustic neuroma, for which all the patients were assessed by CT or MRI; 2) a history of ear surgery affecting the examination of the mastoid; 3) current or past history of otitis media that affected the mastoid pneumatization; 4) current mastoid inflammation, neoplastic lesion or other diseases that could alter the mastoid pneumatization; 5) autoimmune diseases; 6) past history of other types of peripheral vertigo, such as vestibular migraine (VM) alone, benign paroxysmal positional vertigo, central vertigo, psychogenic vertigo, and vertigo caused by systemic disease.

2.3 Ethical considerations

The study was approved by Ethics Committee of Peking University People’s Hospital. All patients provided written informed consent.

2.4 Data collection

A questionnaire was developed based on the criteria of MD revised in 2015, and the third edition of the International Classification of Headache Disorders (ICHD-III) criteria for migraine. Information regarding MD and migraine related-factors were collected through the questionnaire, including age, onset age, gender, history of tinnitus, aural fullness, frequency of vertigo attacks(the mean number of vertigo spells during recent 6 months), triggers of vertigo attacks, and history of migraine. Then all the patients would receive electronic otoscopy and pure tone audiometry to ensure the integrity of the tympanic membrane and identify the degree of hearing loss. All diagnoses were confirmed by senior ENT specialists.

2.5 Evaluation of the mastoid cell system and measurement of the distance between external auditory canal and sigmoid sinus

The mastoid cell system was divided into two types bases on CT scan results: well-pneumatization type and poor-pneumatization type, using the method published by Lin Han in 2013 [16]. Mastoid cell system of the suffering side in MD patients and the poorer side in healthy controls were compared in the study.

The lasso tool of the photoshop software was used to outline the Homarus and exclude the non-air cell system. Three levels, including the upper semicircular canal (Fig. 1), horizontal semicircular canal (Fig. 2) and the posterior semicircular canal (Fig. 3), were selected as standard. The area of the mastoid cell with continuous diameter greater than 2mm were defined as good pneumatization area [The proportion of good pneumatization area = (Pixel sum of good pneumatization area in this 3 layers / Pixel sum of the mastoid cell 3 layers in this 3 layers)×100% ]. The mastoid cell system of the patients were classified as pneumatization type with over 50% good pneumatization area, and sclerotic type with less than 10% good pneumatization area. The rest were diploetic type. In this study, we classified the pneumatization type as well-pneumatization type, the sclerotic and diploetic type as poor-pneumatization type.

Fig. 1

Good pneumatization area in the upper semicircular canal.

Fig. 2

Good pneumatization area in the horizontal semicircular canal.

Fig. 3

Good pneumatization area in the posterior semicircular canal.

The shortest distance between the sigmoid sinus (SS) and the posterior wall of the external auditory canal (EAC) was measured by high resolution computed tomography (CT) scan in the MD patients on the suffering side, and in the healthy control group on the poorer mastoid pneumatization side (Fig. 4). The distance of less than 10mm was diagnosed as anterior displacement of sigmoid sinus (ADSS), according to study published by Serhan in 1995 [4].

Fig. 4

The shortest distance between the sigmoid sinus (SS) and the posterior wall of the external auditory canal (EAC).

2.6 Statistical analysis

The SPSS software (version 23.0, SPSS, IBM, New York, USA) was applied for statistical analysis. Frequencies and percentages were employed to illustrate the distributions, while mean was used to describe the average level. Categorical data and quantitative data were compared respectively by Chi-square tests and T-test. The type of mastoid gasification, the distance between EAC and SS, hearing thresholds, epidemic and clinical characteristics were compared between MD patients with and without migraine. Then generalized linear regression analysis was used to select independent related factors of migraine among patients with MD. All reported p values were two-sided, in which < 0.05 values were considered to indicate statistical significance.

3 Results

3.1 Demographic features and anatomical variations in patients with Meniere’s disease

In total, there were 110 participants with MD, among which 95 patients were included in the final analysis, and 15 patients were excluded based on the exclusion criteria. The female to male ratio was 48 (50.53%) to 47 (49.47%). The mean age of the patients with MD and healthy controls were 56.80±10.99 and 51.08±11.74, respectively.

The results showed that the percentage of MD patients with poor pneumatized mastoid air cell system was much higher compared with healthy controls (72.63% vs 7.37%, p < 0.001). Furthermore, the distance between EAC and SS in MD patients is significantly shorter than healthy controls (11.59±3.09mm vs 12.80±2.99mm, p < 0.05). There was a higher proportion of patients diagnosed with ADSS in MD participants compared to healthy individuals (67.37% vs 18.95%, p < 0.001). (Table 1) However, laterality (Table-2) and gender (Table-3) were found not significantly related to the anatomical variations in the CT scan images during the 95 MD patients.

Table 1
Demographic characteristics and anatomical factors in studied patients with MD and healthy controls

MD patients Healthy controls P values

Age 56.800±10.993 55.460±4.903 0.281

Sex (female) 48/95(50.53%) 54/95(56.84%) 0.380

The distance between 11.591±3.085 12.803±2.986 0.007^*

EAC and SS (mm)

Well-pneumatization 26/95(27.37%) 88/95(92.63%) 0.000^*

mastoid

Poor-pneumatization 69/95(72.63%) 7/95(7.37%)

mastoid

ADSS 64/95(67.37%) 18/95(18.95%) 0.000^*

	MD patients	Healthy controls	P values
Age	56.800±10.993	55.460±4.903	0.281
Sex (female)	48/95(50.53%)	54/95(56.84%)	0.380
The distance between	11.591±3.085	12.803±2.986	0.007^*
EAC and SS (mm)
Well-pneumatization	26/95(27.37%)	88/95(92.63%)	0.000^*
mastoid
Poor-pneumatization	69/95(72.63%)	7/95(7.37%)
mastoid
ADSS	64/95(67.37%)	18/95(18.95%)	0.000^*

Calculated p values were made for comparison between MD patients with healthy controls. EAC: external acoustic canal. SS: sigmoid sinus. ADSS: anterior displacement of sigmoid sinus.

3.2 Demographic features and anatomical variations in patients with Meniere’s disease with and without migraine

All of the ninety-five MD participants were divided into two groups: 54 MD patients coexisted with migraine and 41 patients with MD alone. The results showed that the gender was significantly associated with the presence of migraine, the female accounted for 72.22% of all the patients with MD and migraine.

The data indicated that there were significant differences in the degree of mastoid pneumatization and the proportion of ADSS between the two groups. The percentage of poor-pneumatization mastoid in the group of MD patients with migraine was much higher than MD alone group (81.48% vs 60.98%, p < 0.05). Meanwhile, among these ninety-five MD participants, the incidence of ADSS was 46.30% in MD patients with migraine, compared to 24.39% in MD patients without migraine (P < 0.05). (Table 4)

Table 2
Comparison of bilateral anatomical features of MD patients

Variable Affected side Healthy side p

Mastoid pneumatization

Well-pneumatization mastoid 26/95(27.37%) 24/95(25.26%) 0.119

Poor-pneumatization mastoid 69/95(72.63%) 71/95(74.74%)

ADSS 35/95(36.84%) 25/95(26.32%) 0.742

The distance between 11.591±3.085 11.977±3.061 0.388

EAC and SS(mm)

Variable	Affected side	Healthy side	p
Mastoid pneumatization
Well-pneumatization mastoid	26/95(27.37%)	24/95(25.26%)	0.119
Poor-pneumatization mastoid	69/95(72.63%)	71/95(74.74%)
ADSS	35/95(36.84%)	25/95(26.32%)	0.742
The distance between	11.591±3.085	11.977±3.061	0.388
EAC and SS(mm)

Calculated p values were made for comparison between subgroups of patients with MD. ADSS: anterior displacement of sigmoid sinus.

Table 3

Comparison of anatomical features between male and female during MD patients

Variable	Female	Male	p
Mastoid pneumatization
Well-pneumatization mastoid	9/48(18.75%)	39/47(82.98%)	0.057
Poor-pneumatization mastoid	39/48(81.25%)	30/47(63.83%)
ADSS	31/48(64.58%)	29/47(61.70%)	0.771
The distance between	11.361±2.840	11.826±3.332	0.466
EAC and SS (mm)

Calculated p values were made for comparison between subgroups of patients with MD. ADSS: anterior displacement of sigmoid sinus.

Table 4

Demographic characteristics and anatomical factors between MD patients with and without migraine

Variable	MD patients without migraine	MD patients with migraine	p
Age	55.610±11.599	57.700±10.529	0.361
Age of onset	52.410±11.456	50.070±11.954	0.338
Sex(female)	9/41(21.95%)	39/54(72.22%)	0.000^*
Affected side
Poor-pneumatization mastoid	25/41(60.98%)	44/54(81.48%)	0.026^*
Well-pneumatization mastoid	19/41(46.34%)	10/54(18.52%)	0.000^*
The distance between	11.695±3.042	11.512±3.144	0.776
EAC and SS(mm)
ADSS	10/41(24.39%)	25/54(46.30%)	0.028^*

Calculated p values were made for comparison between subgroups of patients with MD. EAC: external acoustic canal. SS: sigmoid sinus. ADSS: anterior displacement of sigmoid sinus.

3.3 Clinical characteristics in patients with Meniere’s disease with and without migraine

In this study, the results showed that there were significant differences in the frequency of vertigo attacks within a month, history of aural fullness and vertigo attacks, inducement of vertigo attacks and average hearing threshold between MD patients with and without migraine. Whereas, regarding the history of tinnitus, there was no difference shown between the two groups (Table-5).

Among ninety-five MD patients, the average monthly incidence of vertigo attacks in patients with migraine was markedly more frequent as compared to patients without migraine (6.480±2.321 vs. 2.340±1.637, P < 0.001).

The average hearing thresholds of the study participants were listed in Table 5. In MD patients with migraine, they had better hearing results. The average hearing threshold of 0.5, 1.0, 2.0, 4.0 Hz of the MD patients with migraine was 40.15±11.17, compared to 47.195±18.079 in patients with MD alone. Furthermore, pure tone average at 500 Hz was 40.830±11.523 in patients with both MD and migraine, which was much lower than MD patients without migraine 48.900±17.941(p < 0.05).

Table 5
Clinical characteristics related to MD with or without migraine

MD patients without Migraine MD patients with Migraine P value

Frequency of vertigo within a month 2.340±1.637 6.480±2.321 0.000^*

Tinnitus 36/41(87.80%) 42/54(77.78%) 0.161

Aural fullness 36/41(87.80%) 37/54(68.52%) 0.027^*

History of vertigo(years) 3.180±4.078 7.642±11.569 0.011^*

Inducement of vertigo attacks 22/41(53.66%) 41/54(75.93%) 0.023^*

The average hearing threshold 47.195±18.079 40.154±11.170 0.032^*

250 Hz 51.710±16.793 48.150±11.627 0.226

500 Hz 48.900±17.941 40.830±11.523 0.014^*

1000 Hz 47.200±19.591 40.930±12.704 0.079

2000 Hz 45.490±19.805 38.700±13.289 0.063

4000 Hz 57.680±23.825 57.690±24.121 0.758

	MD patients without Migraine	MD patients with Migraine	P value
Frequency of vertigo within a month	2.340±1.637	6.480±2.321	0.000^*
Tinnitus	36/41(87.80%)	42/54(77.78%)	0.161
Aural fullness	36/41(87.80%)	37/54(68.52%)	0.027^*
History of vertigo(years)	3.180±4.078	7.642±11.569	0.011^*
Inducement of vertigo attacks	22/41(53.66%)	41/54(75.93%)	0.023^*
The average hearing threshold	47.195±18.079	40.154±11.170	0.032^*
250 Hz	51.710±16.793	48.150±11.627	0.226
500 Hz	48.900±17.941	40.830±11.523	0.014^*
1000 Hz	47.200±19.591	40.930±12.704	0.079
2000 Hz	45.490±19.805	38.700±13.289	0.063
4000 Hz	57.680±23.825	57.690±24.121	0.758

Calculated p values were made for comparison between subgroups of patients with MD.

3.4 Factors associated with migraine in patients with Meniere’s disease

In this study, we considered age, gender, history of vertigo, frequency of vertigo attacks, the average hearing thresholds, ADSS and pneumatization of mastoid as potential factors influencing migraine presence among MD patients (Table 6). Complete data were available for all ninety-five patients and were analyzed in generalized linear regression analysis. Factors, including age, gender, history of vertigo, frequency of vertigo attacks, the average hearing thresholds, presence of ADSS and degree of pneumatization of mastoid, were included as covariates. The correlation of these independent factors with the presence of migraine among patients with MD were assessed (Table 6).

Table 6
Multi-factors correlated with the occurrence of migraine within MD patients

Migraine

Beta coefficient P values

(95% CI)

Age 0.92(–0.005 to 0.135) 0.358

Female 5.54(0.319 to 0.668) 0.000^*

History of vertigo 2.36(0.002 to 0.023) 0.018^*

Frequency of vertigo attacks 9.73(0.097 to 0.146) 0.000^*

The average hearing threshold 0.99(–0.014 to –0.001) 0.019^*

ADSS 2.23(0.027 to 0.434) 0.026^*

Poor-pneumatization of mastoid 2.26(0.033 to 0.473) 0.024^*

	Migraine
Age	0.92(–0.005 to 0.135)	0.358
Female	5.54(0.319 to 0.668)	0.000^*
History of vertigo	2.36(0.002 to 0.023)	0.018^*
Frequency of vertigo attacks	9.73(0.097 to 0.146)	0.000^*
The average hearing threshold	0.99(–0.014 to –0.001)	0.019^*
ADSS	2.23(0.027 to 0.434)	0.026^*
Poor-pneumatization of mastoid	2.26(0.033 to 0.473)	0.024^*

ADSS: anterior displacement of sigmoid sinus.^*

The results indicated that age was not significantly correlated with migraine. However, factors, such as gender, history of vertigo, frequency of vertigo attacks, the average hearing threshold, presence of ADSS and the degree of mastoid pneumatization, were correlated with the presence of migraine in MD patients. The data showed that female patients with MD were more likely to develop migraine than male MD patients (95% CI, 5.54(0.319 to 0.668); p < 0.000), and the MD patients with long history of vertigo and more frequent vertigo attacks were more susceptible to migraine (95% CI, 2.36(0.002 to 0.023), p = 0.018; 95% CI, 9.73(0.097 to 0.146); p < 0.000). MD patients with a lower average hearing threshold were more likely to be companied with migraine (95% CI, 0.99(–0.014 to –0.001), p = 0.019). Besides, the patients who were diagnosed with ADSS and poor pneumatization of mastoid, had a higher incidence of migraine(95% CI, 2.23(0.027 to 0.434), p = 0.026; 95% CI, 2.26(0.033 to 0.473), p = 0.024).

4 Discussion

In this hospital-based study of patients with MD, the results suggested that the proportion of poor pneumatization of mastoid and ADSS were higher in patients with MD compared to healthy controls. After dividing MD patients into two groups based on coexistence of migraine, there were significant differences between the MD patients with and without migraine, including gender, frequency of vertigo attacks, inducement of vertigo attacks, history of aural fullness, the degree of mastoid pneumatization, the proportion of sigmoid sinus advancement, average hearing loss and the hearing threshold at 500 Hz. By using generalized linear regression analysis, the data indicated factors, including anatomical features, such as degree of mastoid pneumatization and ADSS, average hearing threshold, gender, history of vertigo and frequency of vertigo attacks were associated with the occurrence of migraine among MD patients. The clinical implications of the findings are discussed below.

It is well known that MD has a group of symptoms, which may be the final common pathway of various inner ear diseases instead of the consequence of a single isolated etiology. Multiple genetic or environmental factors could challenge inner-ear homeostasis and trigger a partial or a complete clinical phenotype, depending on the individual susceptibility, according to several regulatory factors such as the inmate immune response, the endocrine system, and the autonomic nervous system [19]. The endolymphatic hydrops has been acknowledged as the main physiological mechanism of MD. Factors, including excessive endolymph production, decreased endolymph absorption, ionic imbalance, genetic abnormalities, viral infection, autoimmune disease, inflammation, dietary factors, vascular irregularities as well as anatomical features, such as peri-saccular fibrosis [34], significantly anterior displacement of the sigmoid sinus and poor pneumatization of mastoid [22, 29], have been reported to contribute to the formation of the endolymphatic hydrops, which are consistent with our study.

Though the exact mechanism of the mastoid pneumatization is poorly understood, it is believed that the mastoid air cell system represented an extensive system of interconnecting air filled cavities arising from the walls of the mastoid antrum and walls of the middle ear [2]. A series of studies indicated the definite impact of chronic middle ear infection on the pneumatization process [3]. Poor pneumatization mastoid may be caused by repeated intermittent inflammatory reactions, namely, patients with ADSS and poor-pneumatization mastoid have a local chronic inflammatory reaction in the inner ear. Some studies have shown that patients with MD have a systemic proinflammatory response [9]. We speculate that the local chronic inflammatory response will further stimulate the ES, the important immunologic defense organ of inner ear, inducing a series of immune responses subsequently, which eventually leads to damage to the inner ear and induces MD. Furthermore, in 2008 Hamed Sajjadi suggested that the anteriorly located sigmoid sinus can cause vascular compression of the endolymphatic sac and then lead to obstruction and hydrops [28]. All above reasons might explain the high proportion of poor mastoid pneumatization and ADSS in patients with MD.

This study also found that the poor-pneumatization mastoid and ADSS appeared to be significantly correlated with the presence of migraine in patients with MD. It is widely accepted that the activity and sensitization of the trigeminovascular system (TVS) can cause migraine [15, 21]. As we mentioned before, MD patients with ADSS and poor-pneumatization mastoid might have a local chronic inflammatory response in the inner ear. Studies have shown that the occurrence of migraine is also related to the inflammatory response [30], so we deem that the local inflammatory response would stimulate the TVS system distributed in the inner ear and induce migraine. Meanwhile, every time migraine attacked, this system would be activated releasing vasoactive neuropeptides from their perivascular endings, mainly through the vestibular-cochlear branch of the trigeminal nerve innervating the blood flow in both the vestibular and cochlea. These vasoactive neuropeptides including substance P(SP), calcitonin gene-related peptide and neurokinin A would cause vasodilation, increase cochlea blood flow, extravasation of plasma protein, release of inflammatory factors and may induce the endolymphatic hydrops eventually [18], a vicious circle.

Apart from the anatomical features including poor pneumatization of mastoid and ADSS, MD patients with and without migraine also differed significantly in clinical manifestations such as history of vertigo, the frequency of vertigo attacks, average hearing threshold especially average hearing threshold at 500 Hz. We speculated that vertigo episodes during patients with MD and migraine were comprised of migrainous vertigo and Meniere vertigo, so the frequency of vertigo attacks was higher and the history of vertigo was longer as compared with patients with MD alone [33]. During MD patients with migraine and without migraine, the frequency of vertigo attacks within a month was 6.48 and 2.34, so we deemed that the proportion of vertigo attacks caused by migraine in the patients with MD and migraine was around 64% (4.14/6.48). As for the better hearing during MD patients with migraine, it is believed that migraine is mainly a central nervous system dysfunction involving the TVS. The trigeminal nerve innervates the cochlea blood vessels through the ophthalmic branch, which can be abnormally activated and release neurotransmitters inducing vasodilation of inner ear blood vessels, extravasation of plasma protein and tissue edema, etc. Furthermore, some scholars believe that vasoactive factors released by the activated TVS [8] would cause local vasodilation of the inner ear blood vessels to alleviate the endolymphatic hydrops and reduce hearing loss. Besides, the patients with MD and migraine were more likely to receive medicine treatment at an earlier stage for the annoyed frequent vertigo attacks, which may also contribute to the lower hearing threshold.

Recently, the coexistence of MD and migraine has drawn more and more attention. Some scholars found that medications used for migraine may improve the quality of life for patients with MD significantly [14], but the relationship between them remains unclear [25, 31]. A study conducted in 2017 suggested whether with migraine accompanied can be used as a clinical classification standard of MD, in which significant differences in epidemiological and clinical features existed between MD patients with and without migraine [13]. This might be explained by the pathophysiological mechanisms of migraine, and further explores are needed. Meanwhile, in 2019, David Bächinger described two histopathological subtypes of MD based on endolymphatic sac(ES) pathology, a degenerating distal ES and a hypoplastic ES [6], and the incidence of migraine was significantly correlated with the dysplasia of vestibular aqueduct.

MD is known as a clinically heterogeneous disease with different phenotypes, so it is of great importance to understand its clinical subtype to get a deeper understanding of its pathology and searching for the specific treatment. A quantity of studies focusing on the subtyping of MD from various aspects such as cytokine profiles, anatomical features and genetics have already been done. Frejo et al have observed two subgroups of MD patients according to their IL-1ß profile in 2018 [12]. The next year Marisa Flook identified IL- 1ß, CCL3, CCL22, and CXCL1 levels as capable of differentiating VM patients from MD patients [11]. In the same year, two histopathological subtypes of MD were described according to the pathology of endolymphatic sac(ES) [6], which were associated with different phenotypes [5]. Furthermore, epidemiological evidence also supports a genetic contribution in MD including racial differences in prevalence [20] and familial clustering [27]. Genes of four main categories: immune-associated, proliferation and cell survival, cell surface channels, and extracellular matrix proteins have been proved to be related to the MD [10].

Consistent with above studies, this study believed that migraine could be used as a standard for the clinical classification of MD. In our study, 54 of 95 patients with MD (56.8%) had a history of or current migraine, which is consistent with many scholars who have reported the co-existence of MD and migraine as defined by the IHS [25]. Apart from the anatomical features including poor pneumatization of mastoid and ADSS, MD patients with and without migraine also differed significantly in clinical manifestations such as history of vertigo, the frequency of vertigo attacks, average hearing threshold especially average hearing threshold at 500 Hz. We hypothesized that maybe we can subtype Meniere disease by whether or not with migraine accompanied as L. Frejo defined 5 clinical subgroups in patients with unilateral Meniere disease in 2017 [13]. In that study, whether accompanied by migraine was used as a classification standard for MD which was consistent with our previous studies [32, 33]. In our previous study, we also found that MD patients with and without migraine could differ significantly in clinical symptoms, audiological characteristics and vascular irregularities.

Of course, our study has certain limitations. First, our hospital locates in the northern China, which might result in selection bias. Second, patients with migraine may firstly been treated in other hospitals and transferred for further treatment to our hospital, resulting in referral bias and an overestimate of the presence of migraine during patients with MD. Thirdly, the study is a retrospective clinical study, in which all of the patients chosen were hospitalized in our department for surgery so they were all in an advanced stage with a relative long history, which might result in the recall bias of the onset age with previous study. Furthermore, the comparatively small quantity of cases in this study prevented us from comparing MD women with and without migraine, which resulted in the interference caused by gender could not be completely removed. Finally, this study did not include a genetic factor or familial condition in the analysis which need further research conducted in the future.

5 Conclusion

Our study confirmed that a relationship existed between MD and anatomical features including mastoid pneumatization and ADSS. Patients with MD had a poor pneumatization mastoid and were more prone to be accompanied by ADSS compared with healthy controls. Moreover, anatomical features including poor pneumatization mastoid and ADSS as well as several clinical manifestations were proved to be associated with the presence of migraine among patients with MD. We suggest that MD patients with and without migraine are two different clinical subtypes, which may help us get a better understanding of the underlying pathophysiologic mechanisms of Meniere disease and achieve the target of specific treatment strategies. In conclusion, this new clinical subtyping approach might improve the diagnosis, prognosis and clinical decision-making for individual MD patients. More extensive studies are required to explore the clinical subtyping of MD.

Footnotes

Acknowledgments

This work was supported by Peking University People’s Hospital Scientific Research Development Funds (RDY2019–04).

Conflict of interest statement

None conflict of interest

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	Migraine
Beta coefficient	P values
	(95% CI)
Age	0.92(–0.005 to 0.135)	0.358
Female	5.54(0.319 to 0.668)	0.000^*
History of vertigo	2.36(0.002 to 0.023)	0.018^*
Frequency of vertigo attacks	9.73(0.097 to 0.146)	0.000^*
The average hearing threshold	0.99(–0.014 to –0.001)	0.019^*
ADSS	2.23(0.027 to 0.434)	0.026^*
Poor-pneumatization of mastoid	2.26(0.033 to 0.473)	0.024^*