Section 2 Etiopathogenesis

**10**

*Meniere's Disease*

**References**

[1] Members of the Committee on Hearing and Equilibrium. Committee on hearing and equilibrium, guidelines for the diagnosis and evaluation of therapy in Ménière's disease. Otolaryngology– Head and Neck Surgery. 1995;**113**:181-185 [9] Lamounier P, Gobbo DA, de Souza TSA, de Oliveira CACP, Bahmad F. Electrocochleography for Ménière's disease: Is it reliable? Brazilian

Journal of Otorhinolaryngology.

for drop attacks in patients with Ménière's disease. Laryngoscope.

2014;**124**(9):2151-2154

[10] Viana LM, Bahmad F Jr, Rauch SD. Intratympanic gentamicin as a treatment

2014;**80**:527-532

[2] Lopez-Escamez JA et al. Diagnostic criteria for Ménière's disease. Journal of

Vestibular Research. 2015;**25**:1-7

[3] Oliveira CA, Bahmad F Jr, Sampaio AL. Ménière's Disease. In: Textbook of Vertigo - Diagnosis & Management. 1st ed. Vol. 01. New Delhi: Jaypee Brothers Medical Publishers;

[4] Rauch SD, Merchant SN,

Thedinger BA. Ménière's syndrome and endolymphatic hydrops: Double-blind temporal bone study. The Annals of Otology, Rhinology, and Laryngology.

[5] Merchant SN, Adams JC, Nadol JB. Pathophysiology of Ménière' syndrome are symptoms caused by endolymphatic hydrops? Otology & Neurotology.

[6] Agrawal Y, Minor LB. Ménière disease and other causes of episodic vertigo. In: Bronstein AM, editor. Vertigo and Imbalance. United Kingdom: Oxford; 2013. pp. 241-250

[7] Bahmad F Jr, DePalma SR,

[8] Cal R, Bahmad F Jr. Migraine associated with disfunção auditivovestibular auditory-vestibular

dysfunction. BJORL. 2008;**74**(4):606-612

2009;**118**(9):670-676

Merchant SN, Bezerra RL, Oliveira CA, Seidman CE, et al. Locus for familial migrainous vertigo disease maps to chromosome 5q35. The Annals of Otology, Rhinology, and Laryngology.

2014. pp. 62-93

1989;**98**:873-883

2005;**26**:74-81

**13**

**1. Introduction**

disease that will be considered here.

Menière's disease and will be our subject in this chapter.

**Chapter 2**

**Abstract**

Menière's Disease:

This chapter will discuss idiopathic Menière's syndrome. That is to say—Menière's disease. We will start with a brief recall on the History of Menière's disease beginning with the description of the syndrome by Prosper Menière in 1861, the description of endolymphatic hydrops in temporal bone studies by Hallpike and Cairns in 1938 and by Yamakaua in the same year. Endolymphatic hydrops became a pathologic correlate for Menière's syndrome. Theories that considered endolymphatic hydrops as the cause of the syndrome will be discussed. More recent studies questioning the old theories and thinking of endolymphatic hydrops as an epiphenomenon in the course of the syndrome rather than the cause of the symptoms will be discussed. Temporal bone studies were the basis of these new theories too. Familial Menière's disease will be discussed and several families will be described in detail. Because the phenotype of siblings on each family studied was variable and migraine was present in many affected members of these families a spectrum was postulated going from migraine alone to full blown Menière's disease. Some siblings had what has been described recently as vertiginous migraine and a detailed description of this syndrome will be provided and the differences between this syndrome and Menière's disease will be made clear. About 20% of Menière's disease patients have a familial history. Sporadic Meniere's disease might have a genetic predisposition and other environmental and behavioral factors contribute for the surfacing of the disease (multifactorial etiology). Because migraine is a central phenomenon and the vertiginous episodes and auditory symptoms are peripheral a hypothesis is presented for the pathophysiology of Menière's disease. Recent research comparing vestibular migraine and Manière's disease reinforcing the concept of these syndromes representing a continuum process with similar etiology are discussed at the end.

**Keywords:** Menière's disease (MD), endolymphatic hydrops (EH), migraine,

This chapter will present the etiopathogenesis and pathophysiology of Menière's

We consider Menière's disease the Menière's syndrome without a clear etiology. Because vertigo, tinnitus and hearing loss are present in most of the insults to the inner ear there are many known causes for these symptoms. However, there is the Menière's syndrome present in some patients without any definable etiology. This is

disease (MD). It is necessary therefore to make clear the definition of Menière's

familial Menière's syndrome, continuum, vertiginous migraine (VM)

Etiopathogenesis

*Carlos A. Oliveira*

#### **Chapter 2**

## Menière's Disease: Etiopathogenesis

*Carlos A. Oliveira*

#### **Abstract**

This chapter will discuss idiopathic Menière's syndrome. That is to say—Menière's disease. We will start with a brief recall on the History of Menière's disease beginning with the description of the syndrome by Prosper Menière in 1861, the description of endolymphatic hydrops in temporal bone studies by Hallpike and Cairns in 1938 and by Yamakaua in the same year. Endolymphatic hydrops became a pathologic correlate for Menière's syndrome. Theories that considered endolymphatic hydrops as the cause of the syndrome will be discussed. More recent studies questioning the old theories and thinking of endolymphatic hydrops as an epiphenomenon in the course of the syndrome rather than the cause of the symptoms will be discussed. Temporal bone studies were the basis of these new theories too. Familial Menière's disease will be discussed and several families will be described in detail. Because the phenotype of siblings on each family studied was variable and migraine was present in many affected members of these families a spectrum was postulated going from migraine alone to full blown Menière's disease. Some siblings had what has been described recently as vertiginous migraine and a detailed description of this syndrome will be provided and the differences between this syndrome and Menière's disease will be made clear. About 20% of Menière's disease patients have a familial history. Sporadic Meniere's disease might have a genetic predisposition and other environmental and behavioral factors contribute for the surfacing of the disease (multifactorial etiology). Because migraine is a central phenomenon and the vertiginous episodes and auditory symptoms are peripheral a hypothesis is presented for the pathophysiology of Menière's disease. Recent research comparing vestibular migraine and Manière's disease reinforcing the concept of these syndromes representing a continuum process with similar etiology are discussed at the end.

**Keywords:** Menière's disease (MD), endolymphatic hydrops (EH), migraine, familial Menière's syndrome, continuum, vertiginous migraine (VM)

#### **1. Introduction**

This chapter will present the etiopathogenesis and pathophysiology of Menière's disease (MD). It is necessary therefore to make clear the definition of Menière's disease that will be considered here.

We consider Menière's disease the Menière's syndrome without a clear etiology. Because vertigo, tinnitus and hearing loss are present in most of the insults to the inner ear there are many known causes for these symptoms. However, there is the Menière's syndrome present in some patients without any definable etiology. This is Menière's disease and will be our subject in this chapter.

#### **1.1 History of Menière's disease**

Let us start with following the History of MD. In 1861 Prosper Menière suggested that vertigo, tinnitus and hearing loss were symptoms of vestibular organs injury rather than of brain apoplexy. This paper marked the starting point of a discussion that is now almost 180 years old [1].

In 1938 Hallpike and Cairns described in temporal bone histopathology study hydrops of the endolymphatic compartment in patients who had the Menière's symptoms during life. This was a material proof of the inner ear origin of the Menière's syndrome as stated by Menière in 1861 [2]. In the same year Yamakawa in Japan described the same histopathological findings in temporal bones of patients with the Menière's syndrome [3].

From then on, several temporal bone histopathologists [4–6] found endolymphatic hydrops (EH) in temporal bones of patients with the Menière's syndrome. So, EH was established as the pathological correlate of MD.

Schuknecht [7] in 1978 observed rupture of endolymphatic membranes in patients with EH (**Figures 1** and **2**) in temporal bones of patients who had the Menière's syndrome during their life time. Lawrence in 1864 [8] had shown that rupture of Reisner's membrane in one segment of the chinchilla's cochlear duct and consequent mixing of endolymph with perilymph would cause permanent damage to the organ of Corti in the involved segment.

**15**

Menière's disease.

**Figure 2.**

*Menière's Disease: Etiopathogenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

Based on the ruptures of cochlear and vestibular membranes in the hydropic ears Schuknecht proposed that these ruptures and the consequent mixing of endolymph

However, during the year of 1989 Oliveira selected 83 temporal bones of patients who had significant tinnitus during life and tried to find a pathologic correlate for this symptom. Thirty-seven temporal bones had normal histology (44.5%), 23 had EH (27.7%). Among the normal histology bones there were 13 patients who also had episodic vertigo during life. It was notable that 72.2% of the bones had normal histology and EH. He thought of a common cause for MD and EH. In that case EH

Rauch et al. in 1989 [9] studied 26 temporal bones from patients who had MD during their life's time but only 13 of them had EH. **Figures 3** and **4** are from Rauch's paper and express the change in position of EH: from the cause of the symptoms to

Fraysse in 1990 [10] pointed out that EH may be present in several diseases of the inner ear and that MD patients may not have EH present. Merchant et al. in 1995 found 28 temporal bones from patients with MD who had EH but 19 other patients

After the Schuknecht paper EH became more than a pathologic correlate. It was the cause of the Menière's symptoms. For one decade this theory was accepted as true and things appeared to be settled down regarding the etiopathology of

*Membrane ruptures in the semicircular canal and cochlea duct. Reprinted with permission from Ref. [7].*

would not be the cause for MD but both would have a common cause [8].

an epiphenomenon also caused by an unknown primary event.

with EH never had MD symptoms during life [11].

and perilymph would cause the acute Menière's attack.

#### **Figure 2.**

*Meniere's Disease*

**1.1 History of Menière's disease**

with the Menière's syndrome [3].

discussion that is now almost 180 years old [1].

to the organ of Corti in the involved segment.

So, EH was established as the pathological correlate of MD.

*Membrane rupture in the vestibular labyrinth. Reprinted with permission from Ref. [7].*

Let us start with following the History of MD. In 1861 Prosper Menière suggested that vertigo, tinnitus and hearing loss were symptoms of vestibular organs injury rather than of brain apoplexy. This paper marked the starting point of a

In 1938 Hallpike and Cairns described in temporal bone histopathology study hydrops of the endolymphatic compartment in patients who had the Menière's symptoms during life. This was a material proof of the inner ear origin of the Menière's syndrome as stated by Menière in 1861 [2]. In the same year Yamakawa in Japan described the same histopathological findings in temporal bones of patients

From then on, several temporal bone histopathologists [4–6] found endolymphatic hydrops (EH) in temporal bones of patients with the Menière's syndrome.

Schuknecht [7] in 1978 observed rupture of endolymphatic membranes in patients with EH (**Figures 1** and **2**) in temporal bones of patients who had the Menière's syndrome during their life time. Lawrence in 1864 [8] had shown that rupture of Reisner's membrane in one segment of the chinchilla's cochlear duct and consequent mixing of endolymph with perilymph would cause permanent damage

**14**

**Figure 1.**

*Membrane ruptures in the semicircular canal and cochlea duct. Reprinted with permission from Ref. [7].*

Based on the ruptures of cochlear and vestibular membranes in the hydropic ears Schuknecht proposed that these ruptures and the consequent mixing of endolymph and perilymph would cause the acute Menière's attack.

After the Schuknecht paper EH became more than a pathologic correlate. It was the cause of the Menière's symptoms. For one decade this theory was accepted as true and things appeared to be settled down regarding the etiopathology of Menière's disease.

However, during the year of 1989 Oliveira selected 83 temporal bones of patients who had significant tinnitus during life and tried to find a pathologic correlate for this symptom. Thirty-seven temporal bones had normal histology (44.5%), 23 had EH (27.7%). Among the normal histology bones there were 13 patients who also had episodic vertigo during life. It was notable that 72.2% of the bones had normal histology and EH. He thought of a common cause for MD and EH. In that case EH would not be the cause for MD but both would have a common cause [8].

Rauch et al. in 1989 [9] studied 26 temporal bones from patients who had MD during their life's time but only 13 of them had EH. **Figures 3** and **4** are from Rauch's paper and express the change in position of EH: from the cause of the symptoms to an epiphenomenon also caused by an unknown primary event.

Fraysse in 1990 [10] pointed out that EH may be present in several diseases of the inner ear and that MD patients may not have EH present. Merchant et al. in 1995 found 28 temporal bones from patients with MD who had EH but 19 other patients with EH never had MD symptoms during life [11].

#### **Figure 3.**

*Reprinted with permission from Ref. [9]. See text for explanation.*

In this way the rupture theory put forward by Schuknecht is now discarded. Summarizing what has been said above:


**17**

**Figure 5.**

*Ref. [13].*

*Menière's Disease: Etiopathogenesis*

**2. Familial Menière's disease**

occurring in families.

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

Familial MD is not a rare finding. The presence of MD in several siblings of a family points to a genetic etiology for the disease. Studying these families is a way to learn about MD etiology. In this section we will discuss our experience with MD

This research line started up in 1992 [12]. By that time, we saw a patient who was 69 years old and had a full blown Menière's syndrome: severe episodic rotatory vertigo with drop (falling) attacks, tinnitus and fluctuating hearing loss in his right year. These symptoms started up 5 years before we saw him. His drop attacks were severe and several times he hearts himself during falls. Right sided headaches usually preceded the crisis. Audiogram showed low tone sensorineural hearing loss bilateral and flat severe sensorineural hearing loss on the right ear. Left ear had hearing preserved in the frequencies above 500 Hz (**Figure 5A**). VDRL test was negative and glycerol test was positive bilaterally. An endolymphatic sac procedure

*Audiograms of proband (A and B), one daughter and three sons of his (C–F). Reprinted with permission from* 

#### **Figure 4.**

*Reprinted with permission from Ref. [9]. See text for explanation.*

### **2. Familial Menière's disease**

*Meniere's Disease*

**Figure 3.**

In this way the rupture theory put forward by Schuknecht is now discarded.

symptoms. At most it can be taken as a pathologic correlate for MD. A primary unknown cause produces first the symptoms and later EH as an epiphenomenon.

2.Menière's syndrome is indeed a reaction of the inner ear to many insults (infec-

3.EH may be found in the temporal bones from patients with all the above-mentioned insults: it is therefore a common pathologic correlate to many inner ear injuries.

1.EH is present in most cases of MD but it is not the cause of the Menière's

tion, trauma, tertiary syphilis, otosclerosis, autoimmune diseases).

4.We consider as MD the Menière's syndrome without a known cause.

Summarizing what has been said above:

*Reprinted with permission from Ref. [9]. See text for explanation.*

*Reprinted with permission from Ref. [9]. See text for explanation.*

**16**

**Figure 4.**

Familial MD is not a rare finding. The presence of MD in several siblings of a family points to a genetic etiology for the disease. Studying these families is a way to learn about MD etiology. In this section we will discuss our experience with MD occurring in families.

This research line started up in 1992 [12]. By that time, we saw a patient who was 69 years old and had a full blown Menière's syndrome: severe episodic rotatory vertigo with drop (falling) attacks, tinnitus and fluctuating hearing loss in his right year. These symptoms started up 5 years before we saw him. His drop attacks were severe and several times he hearts himself during falls. Right sided headaches usually preceded the crisis. Audiogram showed low tone sensorineural hearing loss bilateral and flat severe sensorineural hearing loss on the right ear. Left ear had hearing preserved in the frequencies above 500 Hz (**Figure 5A**). VDRL test was negative and glycerol test was positive bilaterally. An endolymphatic sac procedure

**Figure 5.**

*Audiograms of proband (A and B), one daughter and three sons of his (C–F). Reprinted with permission from Ref. [13].*

was performed in his right ear and the drop attacks disappeared. Mild dizziness attacks and headache continued but were controlled on medication. Ten years later in June 1090 his hearing in the right ear had worsened (**Figure 5B**) considerably but the drop attacks had not come back and his dizziness was under control. His headache was unchanged.

The heredogram of this family (**Figure 6**) shows that six of seven sons and daughters of this man had the same complaints as their father and the audiograms on four available siblings showed low tone sensorineural hearing loss (**Figure 5C–F**). One offspring from a second marriage of the index patients also had the same complaints. We did not give attention to the headache these patients complained about so we did not classify this symptom properly.

We found several reports of headache associated with both familial and sporadic Menière's syndrome [13–15] but the headache was not well characterized in any.

Two questions were in our minds after we studied the family described above: (1) how often a family history could be elicited from patients with classic Menière's syndrome; (2) what kind of headache was associated with Menière's syndrome? We started to apply to all the patients with Menière's syndrome seen in our clinic a questionnaire with questions about the presence of similar symptoms in their family members as well as about the presence of migraine symptoms.

Through this questionnaire we identified a large family who had typical Menière's syndrome present in some siblings, migraine and Menière's syndrome in others, and only migraine symptoms in others. Considering all siblings affected with these symptoms we arrived to the heredogram displayed in **Figure 7**. The mode of genetic transmission was clearly autosomal dominant [17]. Of course, we knew that in every day clinic work we find more patients with incomplete than with full blown Menière's syndrome. To consider patients with migraine only as affected siblings was an assumption that was supported by continuing the line of thought.

The summary of all symptoms present on 19 affected members of the family is in **Table 1**. It can be seen there the spectrum of symptoms with some of them present and others absent in different patients. The index patient had full blown Menière's syndrome and fluctuating low tone sensorineural hearing loss (**Figure 8**). Three of his sons had intractable migraine who needed hospitalization for treatment sometimes but they lacked Menière's syndrome symptoms at that point. We concluded that: there was a strong association between migraine and Menière's syndrome in this family and both seemed to be transmitted by a single gene in an autosomal dominant mode. From a physiopathology stand point we do not know how the migraine (central) relates to the Menière's symptoms (peripheral).

Now we had a hypothesis: migraine and Menière's syndrome are related and transmitted in an autosomal dominant mode. To further this hypothesis, we set up to answer two questions: (1) How often is the occurrence of familial

#### **Figure 6.**

*Heredogram of the 1992 family. Reprinted with permission from Ref. [13]. Black symbols are affected siblings. Circles are male and square are females.*

**19**

female and two male probands [16].

*Menière's Disease: Etiopathogenesis*

symptom's complex?

*Circles are males and square are females.*

**Figure 7.**

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

Migraine–Menière's syndrome in our population? (2) How is the evolution of these symptoms as time goes by? In other words: what is the Natural History of this

*Heredogram of 1997 family. Reprinted with permission from Ref. [16]. Black symbols are affected siblings.* 

We then started to apply a questionnaire inquiring about the family history of every patient with typical Menière's syndrome seen in our Otology Clinic prospec-

All index patients were required to have typical Menière's syndrome according to the American Academy of Otolaryngology—Head and Neck Surgery criteria. The work up included audiometry, tympanometry, vectoeletronystagmography and a glycerol test in order to seal the diagnosis of idiopathic typical Menière's syndrome (Menière's disease). At this point the included patients were questioned about migraine symptoms. Next the questionnaire about their family history regarding Menière's and migraine's symptoms present in other family members was applied. It is worth to mention that any symptom of one of these syndromes were noted and used to construct the heredogram of each family. Every available affected member

tively beginning in January 1997 and finishing in December 1998.

of these families went through the same work up of the index patients.

migraine symptoms in the affected members as well as demographic data.

variable penetrance of the gene is probably the cause of this variability.

Eight patients with typical, complete Menière's syndrome were collected in 2 years from our otology clinic in Brasília. Six of the eight had positive family history for Menière's and/or migraine. **Table 2** shows that only one index patient had low tone sensorineural hearing loss. All others displayed high tone sensorineural hearing loss in between crisis. **Table 3** shows the presence/absence of Menière's and

Age of the index patients varied from 26 to 63 years old. Symptoms appeared between 15 and 40 years. Six patients had unilateral symptoms and two had both ears affected. Most of the time migraine occurred before the vestibular symptoms, sometimes it came after the vestibular crisis and a minority had migraine unrelated to the vertiginous attack. In six of the eight indices patient's headache fit the classification of the International Headache Society of 1988 as migraine. There were six

**Figures 9**–**11** show heredograms of the six affected families. It is clear from them that the pattern of genetic transmission is autosomal dominant and there is great variability with some siblings having typical Menière's disease and migraine, others having migraine alone and others having symptoms of Menière's syndrome incomplete with or without migraine. If we assume a monogenetic transmission then

#### **Figure 7.**

*Meniere's Disease*

headache was unchanged.

we did not classify this symptom properly.

was performed in his right ear and the drop attacks disappeared. Mild dizziness attacks and headache continued but were controlled on medication. Ten years later in June 1090 his hearing in the right ear had worsened (**Figure 5B**) considerably but the drop attacks had not come back and his dizziness was under control. His

The heredogram of this family (**Figure 6**) shows that six of seven sons and daughters of this man had the same complaints as their father and the audiograms on four available siblings showed low tone sensorineural hearing loss (**Figure 5C–F**). One offspring from a second marriage of the index patients also had the same complaints. We did not give attention to the headache these patients complained about so

Menière's syndrome [13–15] but the headache was not well characterized in any. Two questions were in our minds after we studied the family described above: (1) how often a family history could be elicited from patients with classic Menière's syndrome; (2) what kind of headache was associated with Menière's syndrome? We started to apply to all the patients with Menière's syndrome seen in our clinic a questionnaire with questions about the presence of similar symptoms in their fam-

Through this questionnaire we identified a large family who had typical Menière's syndrome present in some siblings, migraine and Menière's syndrome in others, and only migraine symptoms in others. Considering all siblings affected with these symptoms we arrived to the heredogram displayed in **Figure 7**. The mode of genetic transmission was clearly autosomal dominant [17]. Of course, we knew that in every day clinic work we find more patients with incomplete than with full blown Menière's syndrome. To consider patients with migraine only as affected siblings was an assumption that was supported by continuing the line of thought. The summary of all symptoms present on 19 affected members of the family is in **Table 1**. It can be seen there the spectrum of symptoms with some of them present and others absent in different patients. The index patient had full blown Menière's syndrome and fluctuating low tone sensorineural hearing loss (**Figure 8**). Three of his sons had intractable migraine who needed hospitalization for treatment sometimes but they lacked Menière's syndrome symptoms at that point. We concluded that: there was a strong association between migraine and Menière's syndrome in this family and both seemed to be transmitted by a single gene in an autosomal dominant mode. From a physiopathology stand point we do not know how the

ily members as well as about the presence of migraine symptoms.

migraine (central) relates to the Menière's symptoms (peripheral).

Now we had a hypothesis: migraine and Menière's syndrome are related and transmitted in an autosomal dominant mode. To further this hypothesis, we set up to answer two questions: (1) How often is the occurrence of familial

*Heredogram of the 1992 family. Reprinted with permission from Ref. [13]. Black symbols are affected siblings.* 

We found several reports of headache associated with both familial and sporadic

**18**

**Figure 6.**

*Circles are male and square are females.*

*Heredogram of 1997 family. Reprinted with permission from Ref. [16]. Black symbols are affected siblings. Circles are males and square are females.*

Migraine–Menière's syndrome in our population? (2) How is the evolution of these symptoms as time goes by? In other words: what is the Natural History of this symptom's complex?

We then started to apply a questionnaire inquiring about the family history of every patient with typical Menière's syndrome seen in our Otology Clinic prospectively beginning in January 1997 and finishing in December 1998.

All index patients were required to have typical Menière's syndrome according to the American Academy of Otolaryngology—Head and Neck Surgery criteria. The work up included audiometry, tympanometry, vectoeletronystagmography and a glycerol test in order to seal the diagnosis of idiopathic typical Menière's syndrome (Menière's disease). At this point the included patients were questioned about migraine symptoms. Next the questionnaire about their family history regarding Menière's and migraine's symptoms present in other family members was applied. It is worth to mention that any symptom of one of these syndromes were noted and used to construct the heredogram of each family. Every available affected member of these families went through the same work up of the index patients.

Eight patients with typical, complete Menière's syndrome were collected in 2 years from our otology clinic in Brasília. Six of the eight had positive family history for Menière's and/or migraine. **Table 2** shows that only one index patient had low tone sensorineural hearing loss. All others displayed high tone sensorineural hearing loss in between crisis. **Table 3** shows the presence/absence of Menière's and migraine symptoms in the affected members as well as demographic data.

Age of the index patients varied from 26 to 63 years old. Symptoms appeared between 15 and 40 years. Six patients had unilateral symptoms and two had both ears affected. Most of the time migraine occurred before the vestibular symptoms, sometimes it came after the vestibular crisis and a minority had migraine unrelated to the vertiginous attack. In six of the eight indices patient's headache fit the classification of the International Headache Society of 1988 as migraine. There were six female and two male probands [16].

**Figures 9**–**11** show heredograms of the six affected families. It is clear from them that the pattern of genetic transmission is autosomal dominant and there is great variability with some siblings having typical Menière's disease and migraine, others having migraine alone and others having symptoms of Menière's syndrome incomplete with or without migraine. If we assume a monogenetic transmission then variable penetrance of the gene is probably the cause of this variability.


#### **Table 1.**

*Summary of clinical, laboratory, audiometric, and electronystagmographic findings in 19 affected members of family studied in 1997.\**

**21**

**Figure 8.**

*loss. Reprinted with permission from Ref. [16].*

*Audiograms of the proband of the 1997 family. (A–C) Document fluctuating low tones sensorineural hearing* 

*Menière's Disease: Etiopathogenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

*Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*

*Meniere's Disease*

**20**

**Table 1.**

*family studied in 1997.\**

*\* Reprinted with permission from Ref. [16].*

*Summary of clinical, laboratory, audiometric, and electronystagmographic findings in 19 affected members of* 

#### **Figure 8.**

*Audiograms of the proband of the 1997 family. (A–C) Document fluctuating low tones sensorineural hearing loss. Reprinted with permission from Ref. [16].*


 *Reprinted with permission from Ref. [18].*

#### **Table 2.**

*Summary of audiometric findings in eight probands (2002 paper).\**

#### **Table 3.**

*Summary of clinical, audiometric, and VENG findings in affected members of six families.\**

**23**

**Figure 10.**

**Figure 9.**

From these data we reasoned that:

1.Typical Menière's syndrome is not very frequent in Brasília: during 2 years in a

*Heredograms of families 5 and 6 of the 2002 paper. The pattern of symptoms distribution among the siblings are* 

2.On the other hand, the occurrence of familial disease in patients with typical Menière's syndrome (Menière's disease) is quite high (six of eight index

*Heredograms of families 3 and 4 from the 2002 paper. Note the spectrum of migraine and Menière's syndrome* 

*present in the affected siblings. Reprinted with permission from Ref. [18].*

very buzzy Otology Clinic we collected only eight cases.

*similar to the one present in families 3 and 4 above. Reprinted with permission from Ref. [18].*

*Menière's Disease: Etiopathogenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

#### *Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*

#### **Figure 9.**

*Meniere's Disease*

**Table 2.**

**22**

**Table 3.**

*\* Reprinted with permission from Ref. [18].*

 *Reprinted with permission from Ref. [18].*

*Summary of audiometric findings in eight probands (2002 paper).\**

*Summary of clinical, audiometric, and VENG findings in affected members of six families.\**

*Heredograms of families 3 and 4 from the 2002 paper. Note the spectrum of migraine and Menière's syndrome present in the affected siblings. Reprinted with permission from Ref. [18].*

#### **Figure 10.**

*Heredograms of families 5 and 6 of the 2002 paper. The pattern of symptoms distribution among the siblings are similar to the one present in families 3 and 4 above. Reprinted with permission from Ref. [18].*

From these data we reasoned that:


patients). If we consider Menière's syndrome all the spectrum of symptoms seen in these families then the disease is not so infrequent. In other words, we see incomplete Menière's syndrome much more often in our clinics than the typical syndrome. However, migraine can be associated with all the Menière`s spectrum of symptoms.

We wanted to ask: what happens to this spectrum of symptoms as time goes by? The family we published in 1997 [17] lived in Brasília and we were able to follow them up from 1995 on for 10 years. The following paragraphs will refer to unpublished data from our group.

All affected and unaffected siblings in the heredogram in **Figure 7** were carefully interviewed along the 10 years follow up. Twenty siblings had no qualitative changes in symptoms from 1995 to 2005. Four had changed from atypical headache in 1995 to typical migraine 10 years later. Two had migraine in 1995 and progressed to Menière's syndrome in 2005. Four siblings had vertigo and atypical headache in 1995 and progressed to vertigo and typical migraine in 2005.

Five unaffected siblings in 1995 had symptoms of the migraine—Menière's complex 10 years later: two with aural fullness, one with migraine, tinnitus, vertigo and hearing loss and two with migraine and vertigo. Three affected siblings had remarkable improvement in migraine and vertigo or complete remission of the symptoms.

Fifteen of the 38 affected siblings started out with migraine and the vestibular symptoms appeared in average 17.6 years later. Seven siblings continued with migraine only after 10 years follow up. Over time the intensity and periodicity of the migraine symptoms tended to diminish and the vestibular symptoms tended to become more frequent and intense (**Table 4** and **Figure 12**).

#### **Figure 11.**

*Heredogram of families 7 and 8 of the 2002 paper. The pattern of symptoms among the siblings is similar to the families 3to 6. Reprinted with permission from Ref. [18].*

**25**

**Patient**

1 2 3 4 5 11 12 21 31 32 33 41 51 52 53 54 55 56 512 524 531 533 541

*\**

*Unpublished observations.*

**Table 4.**

*Natural history of migraine and vestibular symptoms during 10 years follow-up (1997 family) (N = 23 affected siblings).\**

81 90

82 87 92 62 58 69 61 64 63 61 68 66 54 51 51 60 37 37 32 25 29

2/w

—

2/w 1/w 1/w 2/m

2/m

1/m 1/m 3–4/m

1/m

2/w 1/m 1/m

1/m 2/y 3/y 1/m 6/y 1/m

3/y

3/y

4/y

—

2/m 1/m 1/w

—

—

1/m 1/m

—

—

1/w 1/m

—

2/y 3/y 1/y 2/y 1/y —

—

—

1/y

3/y

1/m

4/y

8/10

Moderate

8/10

—

7/10

—

7/10

3/y

—

7/10

—

7/10

2/m 1/m

—

8/10

—

8/10

4/y

8/10

Moderate

8/10

3/y 1/m

1/m

9/10

Moderate

8/10

3/y

8/10

Moderate

6/10

2/y

1/m 1/m

1/m

4/y 1/m

8/10

Moderate

8/10

7/10

Moderate

7/10

—

8/10

—

8/10

2/m

9/10

Severe

8/10

2/m

2/w

9/10

Moderate

7/10

1/m 2/m

1/m

—

10/10

—

6/10

—

9/10

—

6/10

2/m

9/10

Moderate

6/10

1/m

2/m

8/10

Moderate

5/10

2/m 2/m 2/m

—

7/10

—

6/10

1/m

8/10

—

7/10

2/w

9/10

Severe

9/10

1/m

1/w

6/10

Moderate

6/10

—

2/m

1/w

8/10

Moderate

6/10

—

—

—

—

—

Severe

Severe

Severe

Severe

—

Moderate

Moderate

—

—

Severe

Severe

—

Severe

Moderate

Moderate

Moderate

Moderate

—

—

—

Moderate

1/w

1/w

1/w

9/10

Moderate

6/10

Severe

**Age at the moment (2005) (y)**

**Migraine**

**Menière**

**Migraine**

**Menière**

**Migraine**

**Menière**

**Migraine**

**Menière**

**Periodicity\* (1995)**

**Periodicity\* (2005)**

**Intensity (1995)**

**Intensity (2005)**

*Menière's Disease: Etiopathogenesis*

*DOI: http://dx.doi.org/10.5772/intechopen.84698*


### *Menière's Disease: Etiopathogenesis*

*Meniere's Disease*

spectrum of symptoms.

lished data from our group.

the symptoms.

patients). If we consider Menière's syndrome all the spectrum of symptoms seen in these families then the disease is not so infrequent. In other words, we see incomplete Menière's syndrome much more often in our clinics than the typical syndrome. However, migraine can be associated with all the Menière`s

We wanted to ask: what happens to this spectrum of symptoms as time goes by? The family we published in 1997 [17] lived in Brasília and we were able to follow them up from 1995 on for 10 years. The following paragraphs will refer to unpub

All affected and unaffected siblings in the heredogram in **Figure 7** were care

fully interviewed along the 10 years follow up. Twenty siblings had no qualitative changes in symptoms from 1995 to 2005. Four had changed from atypical headache in 1995 to typical migraine 10 years later. Two had migraine in 1995 and progressed to Menière's syndrome in 2005. Four siblings had vertigo and atypical headache in

Five unaffected siblings in 1995 had symptoms of the migraine—Menière's complex 10 years later: two with aural fullness, one with migraine, tinnitus, ver

tigo and hearing loss and two with migraine and vertigo. Three affected siblings had remarkable improvement in migraine and vertigo or complete remission of

symptoms appeared in average 17.6 years later. Seven siblings continued with migraine only after 10 years follow up. Over time the intensity and periodicity of the migraine symptoms tended to diminish and the vestibular symptoms tended to

Fifteen of the 38 affected siblings started out with migraine and the vestibular

*Heredogram of families 7 and 8 of the 2002 paper. The pattern of symptoms among the siblings is similar to the* 

1995 and progressed to vertigo and typical migraine in 2005.

become more frequent and intense (**Table 4** and **Figure 12**).




**24**

**Figure 11.**

*families 3to 6. Reprinted with permission from Ref. [18].*

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

**Table 4.**

#### **Figure 12.**

*Graphic representation of the natural history of this symptom complex during 10 years follow up of the 1997 family.*


**27**

final paper [18].

*Menière's Disease: Etiopathogenesis*

*\*Reprinted with permission from Ref. [19].*

*Hearing loss during 10 years follow-up (N = 19).\**

**Table 5.**

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

Hearing loss worsened in most patients. The loss was in high frequency tones and bilateral (**Table 5**). We were not able to document low tone fluctuating sensorineural hearing loss during the crisis of vertigo/migraine in all siblings but we did

**Patient Audiogram result (1995) Audiogram result (2005)**

512 Normal Mild high frequency SNHL bilaterally

511 — —

521 — — 522 — — 523 — — 524 — — 531 — — 532 — — 533 Normal Normal 541 Normal Normal 542 — — 551 — — 552 — — 553 — —

Now we had the natural history of this complex of symptoms described. We were therefore able to organize the clinical data in order to define a phenotype of

Our hypothesis was that this was a genetically determined symptom complex and the genetic transmission was monogenic with incomplete penetrance. Next step was to try to find the genetic locus for these symptoms. Because we were not able to document low tone sensorineural hearing loss in most of the siblings and the high frequency sensorineural hearing loss was bilateral in the majority of the siblings the clinical diagnosis of migrainous vertigo was adopted for these patients. The fact that some of them had typical Menière's syndrome including low tone sensorineural hearing loss was however pointed out in the

Twenty-three family members who were clinically and audiologically evaluated and had image studies also done had genome wide linkage analysis performed with Affymetrix GeneChip Human Mapping 10K microarrays. Genotyping of family members DNA with microsatellite markers was used to further assess candidate loci

The results of vestibular testing and imaging studies were unremarkable. The genetic analysis defined a 12.0 MB interval on chromosome 5q35 between loci

rs2448795 and D5S2073 that contained the disease gene (logarithm of odd score 4.21). Molecular genetics studies were performed at the Molecular Genetics laboratory

**3. Discussion of above findings and correlation with current literature**

Here we will blend our results with the current literature on the subject and

of Harvard Medical School headed by Professor Jonathan Seidman.

document this feature clearly only in the index patient (**Figure 8**).

this syndrome in the large family from Brasília.

identified from the whole genome scan.

formulate a new hypothesis.

*Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*


#### **Table 5.**

*Meniere's Disease*

**Figure 12.**

*family.*

*Graphic representation of the natural history of this symptom complex during 10 years follow up of the 1997* 

2 Mild high frequency SNHL Mild to moderate high frequency SNHL 3 Moderate high frequency SNHL Moderate high frequency SNHL 4 Moderate mixed hearing loss bilaterally Moderate mixed hearing loss bilaterally

32 Normal Mild high frequency SNHL bilaterally

41 Mild high frequency SNHL Mild to moderate high frequency SNHL

54 Mild high frequency SNHL bilaterally Mild to moderate high frequency SNHL

55 Mild high frequency SNHL bilaterally Mild to moderate high frequency SNHL

56 Moderate high frequency SNHL Profound high frequency SNHL

Profound mixed hearing loss bilaterally

Moderate to severe high frequency SNHL

bilaterally

bilaterally

bilaterally

bilaterally

bilaterally

bilaterally

Profound high frequency SNHL

**Patient Audiogram result (1995) Audiogram result (2005)**

1 Moderate to profound mixed hearing loss bilaterally

5 Moderate high frequency SNHL bilaterally

11 Normal Normal 12 Normal Normal 13 — — 21 Normal Normal 22 — — 23 — — 24 — — 31 — —

33 — —

42 — — 43 — —

52 Normal Normal 53 Normal Normal

51 Moderate high frequency SNHL bilaterally

**26**

*Hearing loss during 10 years follow-up (N = 19).\**

Hearing loss worsened in most patients. The loss was in high frequency tones and bilateral (**Table 5**). We were not able to document low tone fluctuating sensorineural hearing loss during the crisis of vertigo/migraine in all siblings but we did document this feature clearly only in the index patient (**Figure 8**).

Now we had the natural history of this complex of symptoms described. We were therefore able to organize the clinical data in order to define a phenotype of this syndrome in the large family from Brasília.

Our hypothesis was that this was a genetically determined symptom complex and the genetic transmission was monogenic with incomplete penetrance. Next step was to try to find the genetic locus for these symptoms. Because we were not able to document low tone sensorineural hearing loss in most of the siblings and the high frequency sensorineural hearing loss was bilateral in the majority of the siblings the clinical diagnosis of migrainous vertigo was adopted for these patients. The fact that some of them had typical Menière's syndrome including low tone sensorineural hearing loss was however pointed out in the final paper [18].

Twenty-three family members who were clinically and audiologically evaluated and had image studies also done had genome wide linkage analysis performed with Affymetrix GeneChip Human Mapping 10K microarrays. Genotyping of family members DNA with microsatellite markers was used to further assess candidate loci identified from the whole genome scan.

The results of vestibular testing and imaging studies were unremarkable. The genetic analysis defined a 12.0 MB interval on chromosome 5q35 between loci rs2448795 and D5S2073 that contained the disease gene (logarithm of odd score 4.21).

Molecular genetics studies were performed at the Molecular Genetics laboratory of Harvard Medical School headed by Professor Jonathan Seidman.

#### **3. Discussion of above findings and correlation with current literature**

Here we will blend our results with the current literature on the subject and formulate a new hypothesis.

It is important to acknowledge the recently described vertiginous migraine (VM) syndrome [19] which is now listed in the Barany Society and the International Headache Society classification of vestibular diseases [20]. This entity is very frequent, second only to benign paroxistic positional vertigo being probably present in 1% of the general population [8]. We are not going to describe in detail the VM symptoms but it is important to point out the differences between MD and VM.

One marked difference is the absence of hearing loss that fluctuates in the low frequencies in the beginning and that progresses to severe hearing loss along the life in Menière's disease but not in vertiginous migraine. Bilaterally of the symptoms seems to be more frequent in familial MD and VM than in sporadic MD but it is not different between these two syndromes.

There is a significant body of literature dealing with the interfaces of Menière's disease (DM) and VM. We will review briefly some papers on this subject.

Neuhauser et al. [21, 22] prospectively evaluated migraine in 200 patients from a dizziness clinic and 200 ones from a migraine clinic. Prevalence of migraine that satisfied the criteria of the International Headache Society (HIS) II was 38% in the dizziness clinic and 24% in sex and age matched controls (p < 0.01). Vertiginous migraine was present in 7% of patients in the dizziness clinic and 9% of the ones in the migraine clinic. In 15 of 32 patient's vertigo was always associated with migraine during the acute attacks. In 16 patients this association was sporadic and two patients never had both symptoms together.

Radke et al. [23] studied 78 patients (40 male and 38 female) aged 29–81 years all with idiopathic uni- or bilateral Menière's disease according to the AAO-HNS criteria. Lifetime prevalence of migraine with and without aura was 50% among these patients and 25% among normal control patients (p < 0.001). Furthermore 45% or the Menière's disease patients always experienced at least one migraine symptom (headache, photophobia, aura) during the acute attacks. They postulated a pathophysiologic link between migraine and MD.

Urkur et al. [24] studied VEMPs parameters in VM, MD and migraine patients and found very similar results for all these patients. Gazques et al. [13] published a paper on recent advances in the genetics of recurrent vertigo including familiar episodic ataxias and MD. They found that 20% of MD patients have positive family histories for this disease [25].

Cha et al. [27] described six families with index patients affected by MD and migraine. There were 56 affected siblings. Of these 26 (41%) met the HIS criteria for migraine. Fifty percent had migraine with aura. Three patients had typical aura without headache. Sixty-three family members had recurrent spells of spontaneous vertigo. There were three twin pairs, two monos and one dizygotic. One of the homozygotic pair had migraine and MD while the other one had migraine and episodic vertigo without auditory involvement (VM).

Bertora and Bergman [38] using quantitative EEG (qEEG) studied 120 patients with MD and migraine and 85 patients with MD and no migraine. Eighty-five percent of MDs patients had hemodynamic brain variations like the ones found in migraine. Brain electric depolarizations and cortical irritative focuses are common to migraine and MD. However, MDs patients had important hyperactivity in the limbic lobe [28].

From this brief review of literature, we can say:


**29**

*Menière's Disease: Etiopathogenesis*

between MD and VM.

entity compared to MD.

**4. Conclusion**

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

for c/o VEMP were no different in VM and MD patients.

Recently Welfang et al. [29] selected 30 classic MD patients and 30 patients with definite or probable VM matched by age and sex. Three-dimensional real inversion recovery magnetic resonance (3D real IR) was performed in these patients 24 hours after intratympanic gadolinium injection in order to assess endolymphatic hydrops (EH). Response rates, amplitudes, latency and response thresholds of cervical and ocular evoked myogenic potentials (c/o VEMP) were tested using air conducted sound. Pure tone audiometry was used to evaluate the level of hearing loss. Different degrees of EH were observed in the cochlea and vestibule of MD patients. Some VM patients had 3D real—IR suspicious for cochlea EH and no EH was found in the vestibule of these patients. There was statistically significant correlation between EH and low tone sensorineural hearing loss. Response thresholds

Therefore, low frequencies sensorineural hearing loss correlate with EH on MD patients. 3R-real IR showed more severe degrees of EH in patients with MD but suggestion of EH in the cochlea of VM patients was showed. MD and VM patients behaved similarly in vestibular dysfunction and their transduction pathway (VEMP). Ghawany et al. [30] treated 25 patients with typical MD following protocol to prophylactic migrainous treatment and showed marked improvement in quality of life in 92% of the patients. He states his results point to etiopathogenetic relation

These results suggest a common etiopathogenesis for MD and VM and that VM

At this point we know that the spectrum of symptoms that goes from migraine alone to migraine with full blown MD including vertigo and migraine (VM), vertigo alone (atypical Menière's syndrome) has high familial incidence and is genetically transmitted in a monogenic autosomal dominant mode [16]. We have found that the

Studies using VEMP [26] and 3D real IR [27] have shown that EH is present in different degrees in both MD and VM. It may be that absence of low tone sensorineural hearing loss in VM relates to the very small degree of EH present in this

Based on all this evidence we have up to now we believe that future efforts should be directed to isolate the gene in chromosome 5q35 and follow up longitudinally patients with VM with VEMP and 3D real IR MRI to test the hypothesis that

Sporadic MD and VM should be tested for the presence of the gene we are looking for after we have it isolated. Then we might also have a better idea about the etiology of MD and VM. Probably environmental factors [31] will be also important

Finally we must consider how migraine, a central syndrome relates to Meniere's

Several authors [32–36] have shown that trigeminal vasomotor fibers innervate

disease a syndrome that originates in the periphery of the vestibular system.

the inner ear (stria vascularis, cells of the ampullary crests) and through this pathway the vascular changes occurring in the central nervous system reach the

may progress to MD as time goes by if EH develops in VM patients.

locus for this spectrum of symptoms maps to chromosome 5q35 [18].

VM and MD are different stages of the same process.

for the full development of the disease (multifactorial etiology). We do believe that this research line should be taken to its future.

**5. Etiopathogenesis of migraine—Menière's disease**

3.Migraine is present in both syndromes.

#### *Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*

*Meniere's Disease*

different between these two syndromes.

patients never had both symptoms together.

a pathophysiologic link between migraine and MD.

episodic vertigo without auditory involvement (VM).

From this brief review of literature, we can say:

histories for this disease [25].

common-genetic link.

between these two syndromes.

3.Migraine is present in both syndromes.

It is important to acknowledge the recently described vertiginous migraine (VM) syndrome [19] which is now listed in the Barany Society and the International Headache Society classification of vestibular diseases [20]. This entity is very frequent, second only to benign paroxistic positional vertigo being probably present in 1% of the general population [8]. We are not going to describe in detail the VM symptoms but it is important to point out the differences between MD and VM. One marked difference is the absence of hearing loss that fluctuates in the low frequencies in the beginning and that progresses to severe hearing loss along the life in Menière's disease but not in vertiginous migraine. Bilaterally of the symptoms seems to be more frequent in familial MD and VM than in sporadic MD but it is not

There is a significant body of literature dealing with the interfaces of Menière's

Neuhauser et al. [21, 22] prospectively evaluated migraine in 200 patients from a dizziness clinic and 200 ones from a migraine clinic. Prevalence of migraine that satisfied the criteria of the International Headache Society (HIS) II was 38% in the dizziness clinic and 24% in sex and age matched controls (p < 0.01). Vertiginous migraine was present in 7% of patients in the dizziness clinic and 9% of the ones in the migraine clinic. In 15 of 32 patient's vertigo was always associated with migraine during the acute attacks. In 16 patients this association was sporadic and two

Radke et al. [23] studied 78 patients (40 male and 38 female) aged 29–81 years all with idiopathic uni- or bilateral Menière's disease according to the AAO-HNS criteria. Lifetime prevalence of migraine with and without aura was 50% among these patients and 25% among normal control patients (p < 0.001). Furthermore 45% or the Menière's disease patients always experienced at least one migraine symptom (headache, photophobia, aura) during the acute attacks. They postulated

Urkur et al. [24] studied VEMPs parameters in VM, MD and migraine patients and found very similar results for all these patients. Gazques et al. [13] published a paper on recent advances in the genetics of recurrent vertigo including familiar episodic ataxias and MD. They found that 20% of MD patients have positive family

Cha et al. [27] described six families with index patients affected by MD and migraine. There were 56 affected siblings. Of these 26 (41%) met the HIS criteria for migraine. Fifty percent had migraine with aura. Three patients had typical aura without headache. Sixty-three family members had recurrent spells of spontaneous vertigo. There were three twin pairs, two monos and one dizygotic. One of the homozygotic pair had migraine and MD while the other one had migraine and

Bertora and Bergman [38] using quantitative EEG (qEEG) studied 120 patients with MD and migraine and 85 patients with MD and no migraine. Eighty-five percent of MDs patients had hemodynamic brain variations like the ones found in migraine. Brain electric depolarizations and cortical irritative focuses are common to migraine and MD. However, MDs patients had important hyperactivity in the limbic lobe [28].

1.VM and MD are very often present in one single family and therefore have a

2.Hearing involvement in MD and not in VM is the main clinical difference

disease (DM) and VM. We will review briefly some papers on this subject.

**28**

Recently Welfang et al. [29] selected 30 classic MD patients and 30 patients with definite or probable VM matched by age and sex. Three-dimensional real inversion recovery magnetic resonance (3D real IR) was performed in these patients 24 hours after intratympanic gadolinium injection in order to assess endolymphatic hydrops (EH). Response rates, amplitudes, latency and response thresholds of cervical and ocular evoked myogenic potentials (c/o VEMP) were tested using air conducted sound. Pure tone audiometry was used to evaluate the level of hearing loss.

Different degrees of EH were observed in the cochlea and vestibule of MD patients. Some VM patients had 3D real—IR suspicious for cochlea EH and no EH was found in the vestibule of these patients. There was statistically significant correlation between EH and low tone sensorineural hearing loss. Response thresholds for c/o VEMP were no different in VM and MD patients.

Therefore, low frequencies sensorineural hearing loss correlate with EH on MD patients. 3R-real IR showed more severe degrees of EH in patients with MD but suggestion of EH in the cochlea of VM patients was showed. MD and VM patients behaved similarly in vestibular dysfunction and their transduction pathway (VEMP).

Ghawany et al. [30] treated 25 patients with typical MD following protocol to prophylactic migrainous treatment and showed marked improvement in quality of life in 92% of the patients. He states his results point to etiopathogenetic relation between MD and VM.

These results suggest a common etiopathogenesis for MD and VM and that VM may progress to MD as time goes by if EH develops in VM patients.

#### **4. Conclusion**

At this point we know that the spectrum of symptoms that goes from migraine alone to migraine with full blown MD including vertigo and migraine (VM), vertigo alone (atypical Menière's syndrome) has high familial incidence and is genetically transmitted in a monogenic autosomal dominant mode [16]. We have found that the locus for this spectrum of symptoms maps to chromosome 5q35 [18].

Studies using VEMP [26] and 3D real IR [27] have shown that EH is present in different degrees in both MD and VM. It may be that absence of low tone sensorineural hearing loss in VM relates to the very small degree of EH present in this entity compared to MD.

Based on all this evidence we have up to now we believe that future efforts should be directed to isolate the gene in chromosome 5q35 and follow up longitudinally patients with VM with VEMP and 3D real IR MRI to test the hypothesis that VM and MD are different stages of the same process.

Sporadic MD and VM should be tested for the presence of the gene we are looking for after we have it isolated. Then we might also have a better idea about the etiology of MD and VM. Probably environmental factors [31] will be also important for the full development of the disease (multifactorial etiology).

We do believe that this research line should be taken to its future.

#### **5. Etiopathogenesis of migraine—Menière's disease**

Finally we must consider how migraine, a central syndrome relates to Meniere's disease a syndrome that originates in the periphery of the vestibular system.

Several authors [32–36] have shown that trigeminal vasomotor fibers innervate the inner ear (stria vascularis, cells of the ampullary crests) and through this pathway the vascular changes occurring in the central nervous system reach the

peripheric vestibular system and bring about the symptoms of MD and EH. This certainly would occur in VM too.

Of course this theory needs experimental confirmation before it can be considered proven. Nevertheless the anatomical pathways are in existence and this is factual evidence towards this theory. The natural history of the symptoms in our families supports it.

Dolowitz [37] has studied a big number of patients with MD and showed that headache is a nuclear symptom in sporadic MD but he did not characterize the headache as igraine so this must be done before we can say that migraine is a constant part of sporadic MD.

#### **Author details**

Carlos A. Oliveira Brasília University Medical School, Brasília, DF, Brazil

\*Address all correspondence to: cacpoliveira@brturbo.com.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**31**

*Menière's Disease: Etiopathogenesis*

**References**

1861;**15**:597-601

1938:2310-2312

1940;**55**:59-66

1978;**40**:15-30

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

[1] Menière P. Memoires sur dês lesions de l`òreille interne donnant lieu a dês symptoms de congestion cerebrale apoplectiforme. GazMedicale de Paris.

Disease. Amsterdam: Kugler and

[12] Oliveira CA. Thinking about tinnitus. The International Tinnitus

[13] Oliveira CA, Braga AM. Meniere's syndrome inherited as an autosomal dominant trait. The Annals of

Otology, Rhinology, and Laryngology.

[14] Brown MR. Meniere's syndrome. Archives of Neurology and Psychiatry.

[15] Brown MR. The factor of heredity in labyrinthine deafness and paroxysmal vertigo (Menière's syndrome). The Annals of Otology, Rhinology, and Laryngology. 1949;**58**:665-670

[16] Oliveira CA, Bezerra RL, Araujo MF, Almeida VF, Messias CI. Meniere's syndrome and migraine: Incidence in one family. The Annals of Otology, Rhinology, and Laryngology.

[17] Bernstein JM. Occurrence of episodic vertigo and hearing loss in families. The Annals of Otology, Rhinology, and Laryngology.

[18] Oliveira CA, Messias CI, Ferrari I. Occurrence of familial Meniere's syndrome and migraine in Brasília.

Merchant SN, Bezerra RL, Oliveira CA, Seidman ES, et al. Locus for familial

[19] Bahmad F Jr, De Palma SR,

[11] Merchant SN, Adams J, Nadol JB Jr. Pathophysiology of Menière's syndrome: Are symptoms caused by endolymphatic hydrops? Otology & Neurotology.

Ghedini; 1989

2005;**26**:74-81

Journal. 1995;**1**:1-4

1992;**101**:590-594

1941;**46**:561-565

1997;**106**:823-829

1965;**74**:1011-1021

2002;**111**:229-236

[2] Hallpike LS, Cairns H. Observations

syndrome. The Journal of Laryngology

[3] Yamakaua KJ. Pathologic changes in a Meniere's patient. Journal of Otolaryngology Society of Japan.

[4] Hallpike LS, Wright HS. Histological findings in case of Menière's disease with remarks on pathologic anatomy and basis of this lesion. The Journal of Laryngology and Otology.

[5] Lindsay JR. Histological studies of Menière's disease. Archives of Otolaryngology. 1994;**37**:853-867

[6] Altman F, Kornfeld M. LXXV histological studies of Meniere's disease. The Annals of Otology, Rhinology, &

[7] Schuknecht HF. A critical evaluation of treatment for Meniere's disease. Journal of Contact Rd ORL Allergy.

Laryngology. 1965;**74**:935-943

[8] Fraysse BG, Alonso A, House WF. Observations on the pathology of Meniere's syndrome. Annals of Otology, Rhinology and Laryngology.

[9] Rauch SD, Merchant SN, Thedinger

endolymphatic hydrops. The Annals of Otology, Rhinology, and Laryngology.

[10] HYS K. In: Nadol JB, editor. Second International Symposium on Meniere's

1980;**89**(Suppl 6):2-22

1989;**98**:873-883

BA. Menière's syndrome and

on the pathology of Meniere's

and Otology. 1938;**53**:625-655

*Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*

#### **References**

*Meniere's Disease*

families supports it.

certainly would occur in VM too.

constant part of sporadic MD.

**30**

**Author details**

Carlos A. Oliveira

provided the original work is properly cited.

Brasília University Medical School, Brasília, DF, Brazil

\*Address all correspondence to: cacpoliveira@brturbo.com.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

peripheric vestibular system and bring about the symptoms of MD and EH. This

Of course this theory needs experimental confirmation before it can be considered proven. Nevertheless the anatomical pathways are in existence and this is factual evidence towards this theory. The natural history of the symptoms in our

Dolowitz [37] has studied a big number of patients with MD and showed that headache is a nuclear symptom in sporadic MD but he did not characterize the headache as igraine so this must be done before we can say that migraine is a [1] Menière P. Memoires sur dês lesions de l`òreille interne donnant lieu a dês symptoms de congestion cerebrale apoplectiforme. GazMedicale de Paris. 1861;**15**:597-601

[2] Hallpike LS, Cairns H. Observations on the pathology of Meniere's syndrome. The Journal of Laryngology and Otology. 1938;**53**:625-655

[3] Yamakaua KJ. Pathologic changes in a Meniere's patient. Journal of Otolaryngology Society of Japan. 1938:2310-2312

[4] Hallpike LS, Wright HS. Histological findings in case of Menière's disease with remarks on pathologic anatomy and basis of this lesion. The Journal of Laryngology and Otology. 1940;**55**:59-66

[5] Lindsay JR. Histological studies of Menière's disease. Archives of Otolaryngology. 1994;**37**:853-867

[6] Altman F, Kornfeld M. LXXV histological studies of Meniere's disease. The Annals of Otology, Rhinology, & Laryngology. 1965;**74**:935-943

[7] Schuknecht HF. A critical evaluation of treatment for Meniere's disease. Journal of Contact Rd ORL Allergy. 1978;**40**:15-30

[8] Fraysse BG, Alonso A, House WF. Observations on the pathology of Meniere's syndrome. Annals of Otology, Rhinology and Laryngology. 1980;**89**(Suppl 6):2-22

[9] Rauch SD, Merchant SN, Thedinger BA. Menière's syndrome and endolymphatic hydrops. The Annals of Otology, Rhinology, and Laryngology. 1989;**98**:873-883

[10] HYS K. In: Nadol JB, editor. Second International Symposium on Meniere's

Disease. Amsterdam: Kugler and Ghedini; 1989

[11] Merchant SN, Adams J, Nadol JB Jr. Pathophysiology of Menière's syndrome: Are symptoms caused by endolymphatic hydrops? Otology & Neurotology. 2005;**26**:74-81

[12] Oliveira CA. Thinking about tinnitus. The International Tinnitus Journal. 1995;**1**:1-4

[13] Oliveira CA, Braga AM. Meniere's syndrome inherited as an autosomal dominant trait. The Annals of Otology, Rhinology, and Laryngology. 1992;**101**:590-594

[14] Brown MR. Meniere's syndrome. Archives of Neurology and Psychiatry. 1941;**46**:561-565

[15] Brown MR. The factor of heredity in labyrinthine deafness and paroxysmal vertigo (Menière's syndrome). The Annals of Otology, Rhinology, and Laryngology. 1949;**58**:665-670

[16] Oliveira CA, Bezerra RL, Araujo MF, Almeida VF, Messias CI. Meniere's syndrome and migraine: Incidence in one family. The Annals of Otology, Rhinology, and Laryngology. 1997;**106**:823-829

[17] Bernstein JM. Occurrence of episodic vertigo and hearing loss in families. The Annals of Otology, Rhinology, and Laryngology. 1965;**74**:1011-1021

[18] Oliveira CA, Messias CI, Ferrari I. Occurrence of familial Meniere's syndrome and migraine in Brasília. 2002;**111**:229-236

[19] Bahmad F Jr, De Palma SR, Merchant SN, Bezerra RL, Oliveira CA, Seidman ES, et al. Locus for familial

migrainous vertigo disease maps to chromosome 5q35. The Annals of Otology, Rhinology, and Laryngology. 2009;**118**:670-676

[20] Neuhauser H, Lempert T. Vestibular migraine. Neurologic Clinics. 2009;**27**(2):379-391

[21] Neuhauser H, Leopold M, von Brevern M, Arnold G, Lempert T. The interrelations of migraine, vertigo and migrainous vertigo. Neurology. 2001;**56**(4):436-441

[22] Lempert T, Olesen JF, Urlan J, Waterson J, Seemungal B, Carey J, et al. Vestibular migraine: Diagnostic criteria. Journal of Vestibular Research. 2012;**22**(4):167-172

[23] Radke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Migraine NH. Meniére's disease: Is there a link? Neurology. 2002;**50**(11):1700-1704

[24] Urkur et al. Migrainous vertigo, Manière's disease and migraine. The Journal of International Advanced Otology. 2003;**9**(3):350-367

[25] Oliveira CA. Editorial. The International Tinnitus Journal. 2014;**19**:2-3

[26] Gazques I, Lopes Escames JA. Genetics of recurrent vertigo and vestibular disorders. Genomics. 2011;**12**(6):443-450

[27] Cha HI, Kane MJ, Baloh RHF. Familial clustering of migraine, episodic vertigo and Meniere's disease. Otology & Neurotology. 2008;**29**(1):93-96

[28] Oliveira CA. Letter to the editor. The International Tinnitus Journal. 2017;**21**(76)

[29] Welfang S, Guo P, Rent T, Wanda G. Magnetic resonance imaging of intratympanic gadolinium helps differentiate vestibular migraine from

Meniere's disease. Laryngoscope. 2017;**127**:2382-2388

[30] Ghawani Y, Haiden YM, Moshtaghi O, Lin HW, Djalilian HD. Evaluating quality of life in patients with Meniere's disease treated as migraine. The Annals of Otology, Rhinology, and Laryngology. 2018;**125**:877-887

[31] Oniki J, Takahashi M, Wada R, Sato R. Comparative study of the daily lifestyle of patients with Meniere's disease and controls. The Annals of Otology, Rhinology, and Laryngology. 2005;**114**(12):927-933

[32] William HC. A review of the literature as to the physiologic dysfunction of Meniere's disease: A new hypothesis as to its fundamental cause. Laryngoscope. 1965;**75**:1661-1669

[33] Torok M. Etiology as a guide in the management of Menière's disease. Laryngoscope. 1982;**92**:237-238

[34] Vass Z, Steyger PI, Hordichok AJ, Taune DR, Jansen D, Nuttal AL. Capsaicin stimulation of the cochlea and electric stimulation of the trigeminal ganglion mediate vascular permeability in cochlear and vertebra-basilar arteries: A possible cause of inner ear dysfunction in headache. Neuroscience. 2001;**103**:189-201

[35] Vass Z, Shore SE, Nuttal AL, Miller JM. Endolymphatic hydrops reduces retrograde labeling of trigeminal innervations to the cochlea. Experimental Neurology. 1998;**151**:241-248

[36] Pondugula ST, Sanneman JD, Wangemann P, Milhaud Marcus DC. Glucocorticoids stimulates cation absorption by semicircular canal duct epithelium via epithelial sodium channel PG. American Journal of Physiology. Renal Physiology. 2004;**286**:1127-1135

**33**

*Menière's Disease: Etiopathogenesis*

1979;**89**:67-77

[37] Dolowitz DA. Menière's—An inner ear seizure. Laryngoscope.

*DOI: http://dx.doi.org/10.5772/intechopen.84698*

[38] Bertora GO, Bergman JM. Menière's disease: Is it a special sort of migraine? Our experience. Archives of Sensology and Neurootology in Science and Practice. 2015. Available from: http:// www.neurootology.otg/proceedings

*Menière's Disease: Etiopathogenesis DOI: http://dx.doi.org/10.5772/intechopen.84698*

[37] Dolowitz DA. Menière's—An inner ear seizure. Laryngoscope. 1979;**89**:67-77

*Meniere's Disease*

2009;**118**:670-676

2009;**27**(2):379-391

2001;**56**(4):436-441

2012;**22**(4):167-172

migrainous vertigo disease maps to chromosome 5q35. The Annals of Otology, Rhinology, and Laryngology. Meniere's disease. Laryngoscope.

[31] Oniki J, Takahashi M, Wada R, Sato R. Comparative study of the daily lifestyle of patients with Meniere's disease and controls. The Annals of Otology, Rhinology, and Laryngology.

[32] William HC. A review of the literature as to the physiologic

[33] Torok M. Etiology as a guide in the management of Menière's disease. Laryngoscope. 1982;**92**:237-238

[34] Vass Z, Steyger PI, Hordichok AJ, Taune DR, Jansen D, Nuttal AL.

in cochlear and vertebra-basilar arteries: A possible cause of inner ear dysfunction in headache. Neuroscience.

[35] Vass Z, Shore SE, Nuttal AL, Miller JM. Endolymphatic hydrops reduces retrograde labeling of trigeminal innervations to the cochlea. Experimental Neurology.

[36] Pondugula ST, Sanneman JD, Wangemann P, Milhaud Marcus DC. Glucocorticoids stimulates cation absorption by semicircular canal duct epithelium via epithelial sodium channel PG. American Journal of Physiology. Renal Physiology.

2001;**103**:189-201

1998;**151**:241-248

2004;**286**:1127-1135

Capsaicin stimulation of the cochlea and electric stimulation of the trigeminal ganglion mediate vascular permeability

dysfunction of Meniere's disease: A new hypothesis as to its fundamental cause. Laryngoscope. 1965;**75**:1661-1669

[30] Ghawani Y, Haiden YM, Moshtaghi O, Lin HW, Djalilian HD. Evaluating quality of life in patients with Meniere's disease treated as migraine. The Annals of Otology, Rhinology, and Laryngology.

2017;**127**:2382-2388

2018;**125**:877-887

2005;**114**(12):927-933

[20] Neuhauser H, Lempert T. Vestibular

migraine. Neurologic Clinics.

[21] Neuhauser H, Leopold M, von Brevern M, Arnold G, Lempert T. The interrelations of migraine, vertigo and migrainous vertigo. Neurology.

[22] Lempert T, Olesen JF, Urlan J, Waterson J, Seemungal B, Carey J, et al. Vestibular migraine: Diagnostic criteria. Journal of Vestibular Research.

[23] Radke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Migraine NH. Meniére's disease: Is there a link? Neurology. 2002;**50**(11):1700-1704

[24] Urkur et al. Migrainous vertigo, Manière's disease and migraine. The Journal of International Advanced Otology. 2003;**9**(3):350-367

[25] Oliveira CA. Editorial. The International Tinnitus Journal.

[26] Gazques I, Lopes Escames JA. Genetics of recurrent vertigo and vestibular disorders. Genomics.

[27] Cha HI, Kane MJ, Baloh RHF. Familial clustering of migraine, episodic vertigo and Meniere's disease. Otology & Neurotology. 2008;**29**(1):93-96

[28] Oliveira CA. Letter to the editor. The International Tinnitus Journal.

[29] Welfang S, Guo P, Rent T, Wanda G.

Magnetic resonance imaging of intratympanic gadolinium helps differentiate vestibular migraine from

2014;**19**:2-3

2017;**21**(76)

2011;**12**(6):443-450

**32**

[38] Bertora GO, Bergman JM. Menière's disease: Is it a special sort of migraine? Our experience. Archives of Sensology and Neurootology in Science and Practice. 2015. Available from: http:// www.neurootology.otg/proceedings

Section 3

Nonsurgical Treatment

**35**

Section 3
