Intratympanic Treatment for Meniere's Disease

**67**

**Chapter 4**

**Abstract**

Therapy

The Treatment of Meniere's

*Maria Stella A. Amaral, Henrique F. Pauna,* 

*Ana Claudia M.B. Reis and Miguel A. Hyppolito*

**Keywords:** Meniere's disease, vestibulopathy, vertigo treatment,

and a lower incidence of 17/100,000 per year in Japan [3].

Meniere's disease (MD) is a clinical entity characterized by episodic vertigo, fluctuant sensorineural hearing loss (SNHL), tinnitus, and a pressure sensation of the ear. It can happen uni- or bilaterally, and diagnosis is made clinically, according to the classification of the American Academy of Otolaryngology—Head and Neck Surgery, updated in 2015 (**Table 1**) [1, 2]. MD is a chronic condition affecting about 190/100,000 patients in US, a general incidence about 50–200/100,000 per year,

The diagnosis of MD remains eminently clinical and its manifestations are widely variable. Many patients have audiological symptoms, some have mainly vestibular complaints and few patients have a combination of auditory and vestibular symptoms. The bilateral involvement can be observed in 10–50% of the patients, which leads to a condition difficult to treat and with unfavorable prognosis [4].

chemical labyrinthectomy, vestibulotoxicity

**1. Introduction**

Meniere's disease represents one of the most frequent vestibulopathy, with prevalence of 46–200 cases per 100,000, without difference between genders and manifests in fourth decade of life. Features include dizziness/vertigo, hearing loss, tinnitus, and ear fullness. Individuals with Meniere's disease have poor quality of life due to dizziness, regarding physical, functional, and emotional aspects. The therapeutic measures are proposed, depending on the stage of the disease. About 95% of the patients are well controlled with conservative clinical treatment. The remaining 5% have incapacitating symptoms. These patients are candidates for surgical treatments classics, decompression of the endolymphatic sac, vestibular neurectomy, or labyrinthectomy. Intratympanic gentamicin injections emerged as an alternative to surgical treatments, whose risk and benefit ratio has been shown to be much more satisfactory. Aminoglycosides, such as gentamicin have been used since the decade of 1950 for the vestibular chemical ablation in cases of intractable vertigo. The drawback is that gentamicin causes irreversible destruction to cochlear hair cells with hearing loss. The selective vestibulotoxicity in the treatment of Meniere's disease can be used in the treatment of the vertigo promoting a chemical labyrinthectomy.

Disease by the Intratympanic

#### **Chapter 4**

## The Treatment of Meniere's Disease by the Intratympanic Therapy

*Maria Stella A. Amaral, Henrique F. Pauna, Ana Claudia M.B. Reis and Miguel A. Hyppolito*

#### **Abstract**

Meniere's disease represents one of the most frequent vestibulopathy, with prevalence of 46–200 cases per 100,000, without difference between genders and manifests in fourth decade of life. Features include dizziness/vertigo, hearing loss, tinnitus, and ear fullness. Individuals with Meniere's disease have poor quality of life due to dizziness, regarding physical, functional, and emotional aspects. The therapeutic measures are proposed, depending on the stage of the disease. About 95% of the patients are well controlled with conservative clinical treatment. The remaining 5% have incapacitating symptoms. These patients are candidates for surgical treatments classics, decompression of the endolymphatic sac, vestibular neurectomy, or labyrinthectomy. Intratympanic gentamicin injections emerged as an alternative to surgical treatments, whose risk and benefit ratio has been shown to be much more satisfactory. Aminoglycosides, such as gentamicin have been used since the decade of 1950 for the vestibular chemical ablation in cases of intractable vertigo. The drawback is that gentamicin causes irreversible destruction to cochlear hair cells with hearing loss. The selective vestibulotoxicity in the treatment of Meniere's disease can be used in the treatment of the vertigo promoting a chemical labyrinthectomy.

**Keywords:** Meniere's disease, vestibulopathy, vertigo treatment, chemical labyrinthectomy, vestibulotoxicity

#### **1. Introduction**

Meniere's disease (MD) is a clinical entity characterized by episodic vertigo, fluctuant sensorineural hearing loss (SNHL), tinnitus, and a pressure sensation of the ear. It can happen uni- or bilaterally, and diagnosis is made clinically, according to the classification of the American Academy of Otolaryngology—Head and Neck Surgery, updated in 2015 (**Table 1**) [1, 2]. MD is a chronic condition affecting about 190/100,000 patients in US, a general incidence about 50–200/100,000 per year, and a lower incidence of 17/100,000 per year in Japan [3].

The diagnosis of MD remains eminently clinical and its manifestations are widely variable. Many patients have audiological symptoms, some have mainly vestibular complaints and few patients have a combination of auditory and vestibular symptoms. The bilateral involvement can be observed in 10–50% of the patients, which leads to a condition difficult to treat and with unfavorable prognosis [4].


#### **Table 1.**

*Criteria of diagnosis of MD.*

### **2. Otopathology**

Prosper Meniere, who worked as a director of the first school for the deaf-mute in Paris, described in 1861, a combination of vertigo, imbalance, and hearing impairment reflecting an inner ear disease [1]. But, only in 1937, with the discovery of endolymphatic hydrops (EH) in human temporal bones by Yamakawa and Hallpike and Cairns, the pathologic displacement of Reissner's membrane into the scala vestibuli—and so with the dilation of the scala media of the cochlea—was first stablished (**Figure 1**) [5].

#### **Figure 1.**

*Reissner's membrane displaced in a temporal bone with hydrops (arrowheads).*

#### **Figure 2.**

*Membranous structures displaced in MD. The arrowhead points the membranous structure called saccule, in different stages of hydrops (A, normal; B, slight; C, moderate; and D, severe). FN-facial nerve; S-stapes.*

**69**

*The Treatment of Meniere's Disease by the Intratympanic Therapy*

Many other disorders can be related with hydrops, as aforementioned: temporal bone fracture, otosclerosis, diabetes mellitus, syphilis, hormonal disorders, migraine, and others. Diseases that can cause MD are as follows: food allergy, dyslipidemia, and autoimmune diseases [3, 6]. These disorders can also affect inner ear composition and displace in various degrees other membranous structures, including saccule, utricle, and the ampullae of the semicircular canals (**Figure 2**) [5].

Several tests and evaluation methods have been employed for the diagnosis of MD. These include audiological tests, vestibular, radiological, clinical, and biochemical parameters. However, the lack of a definitive diagnostic test makes the process of diagnosis sometimes longer or frustrating. For this reason, the professional should be well experienced in the decision of when and what test should be used for the diagnostic process and, especially, to know how to interpret the results [7].

Although MD is not a rare condition, there is a delay in the diagnosis. Probably this is due to factors such as the difficulty of the differential diagnosis between other inner ear diseases, mainly due to the occurrence of nonspecific symptoms in the early stages of the disease and the absence of specific tests, in addition to the floating characteristic of MD which hinders the interpretation of the tests [8]. Patients with hearing loss and balance disorders are commonly diagnosed as having MD, which sometimes characterizes a diagnostic error, due to the lack of

The main objective of early diagnosis is the early intervention, aiming to reduce the frequency and intensity of the crisis of vertigo and, at the same time, to preserve the hearing and vestibular functions [7]. Nonetheless, it is common among patients with MD, psychological suffering and loss in quality of life due to the crisis of vertigo [9, 10]. Some procedures significantly collaborate for the diagnosis of MD; however, it is important to emphasize the correlation of clinical history and symptoms with the results of the behavioral evaluation and testing goals for the conclusion of the case. In MD, a progressive hearing loss occurs with disappearance of vertigo in 70% of cases. In addition, the audiological evaluation is important in monitoring treatment, as

Tonal threshold audiometry is the basic examination used in the process of diagnosis and follow-up of MD and has a decisive role in treatment decisions. The progressive sensorineural hearing loss, with impairment of low frequencies and the

The degree of hearing loss seems to be related to the stage of the disease and has a relationship with the symptomatic period. It is common for MD patients a sensorineural hearing loss to moderate to severe before or on the first diagnosis. The settings of the hearing loss may vary; the most common is the ascendant or inverted "U." The flat configuration appears in more advanced stages of the disease. However, different audiometric results can be found and variations in the degree and configuration of hearing loss may be observed, depending on the stage of the disease. Although the low frequencies are generally more affected, hearing loss may be present in all frequencies when in an advanced state of the disease, configuring sometimes an audiogram with flat curve [11]. In this way, the diagnosis of MD should not be established in accordance with the configuration of the audiogram, because there is not a specific audiometric pattern [12]. There is no consensus in the literature that the auditory thresholds for pure tone should be investigated, including thresholds of air and bone conduction and, at least for the frequencies 250 Hz–8 kHz. A difference ≥10 dB is accepted as the float hearing for the MD.

in the case of chemistry labyrinthectomy with gentamicin.

fluctuations, is typical result observed in MD.

*DOI: http://dx.doi.org/10.5772/intechopen.84752*

**3. Audiological findings**

specific diagnostic tests [7, 8].

Many other disorders can be related with hydrops, as aforementioned: temporal bone fracture, otosclerosis, diabetes mellitus, syphilis, hormonal disorders, migraine, and others. Diseases that can cause MD are as follows: food allergy, dyslipidemia, and autoimmune diseases [3, 6]. These disorders can also affect inner ear composition and displace in various degrees other membranous structures, including saccule, utricle, and the ampullae of the semicircular canals (**Figure 2**) [5].

#### **3. Audiological findings**

*Meniere's Disease*

*\**

**Table 1.**

Definite Two or more episodes of vertigo\*

*Defined as spontaneous, rotational vertigo lasting 20 min to 12 h.*

diagnosis

**2. Otopathology**

*\*\*Hearing, tinnitus, or fullness.*

*Criteria of diagnosis of MD.*

**68**

**Figure 2.**

**Figure 1.**

*Reissner's membrane displaced in a temporal bone with hydrops (arrowheads).*

*Membranous structures displaced in MD. The arrowhead points the membranous structure called saccule, in different stages of hydrops (A, normal; B, slight; C, moderate; and D, severe). FN-facial nerve; S-stapes.*

Prosper Meniere, who worked as a director of the first school for the deaf-mute in Paris, described in 1861, a combination of vertigo, imbalance, and hearing impairment reflecting an inner ear disease [1]. But, only in 1937, with the discovery of endolymphatic hydrops (EH) in human temporal bones by Yamakawa and Hallpike and Cairns, the pathologic displacement of Reissner's membrane into the scala vestibuli—and so with the dilation of the scala media of the cochlea—was first stablished (**Figure 1**) [5].

Probable Two or more episodes of vertigo or dizziness, each lasting 20 min to 24 h; fluctuating aural

symptoms\*\* in the affected ear; other causes excluded

plus audiometrically confirmed low- to medium-frequency

SNHL in one ear on at least one occasion before, during, or after one of the episodes of vertigo; fluctuating aural symptoms\*\* in the affected ear; not better accounted for by another vestibular

> Several tests and evaluation methods have been employed for the diagnosis of MD. These include audiological tests, vestibular, radiological, clinical, and biochemical parameters. However, the lack of a definitive diagnostic test makes the process of diagnosis sometimes longer or frustrating. For this reason, the professional should be well experienced in the decision of when and what test should be used for the diagnostic process and, especially, to know how to interpret the results [7].

Although MD is not a rare condition, there is a delay in the diagnosis. Probably this is due to factors such as the difficulty of the differential diagnosis between other inner ear diseases, mainly due to the occurrence of nonspecific symptoms in the early stages of the disease and the absence of specific tests, in addition to the floating characteristic of MD which hinders the interpretation of the tests [8].

Patients with hearing loss and balance disorders are commonly diagnosed as having MD, which sometimes characterizes a diagnostic error, due to the lack of specific diagnostic tests [7, 8].

The main objective of early diagnosis is the early intervention, aiming to reduce the frequency and intensity of the crisis of vertigo and, at the same time, to preserve the hearing and vestibular functions [7]. Nonetheless, it is common among patients with MD, psychological suffering and loss in quality of life due to the crisis of vertigo [9, 10].

Some procedures significantly collaborate for the diagnosis of MD; however, it is important to emphasize the correlation of clinical history and symptoms with the results of the behavioral evaluation and testing goals for the conclusion of the case. In MD, a progressive hearing loss occurs with disappearance of vertigo in 70% of cases.

In addition, the audiological evaluation is important in monitoring treatment, as in the case of chemistry labyrinthectomy with gentamicin.

Tonal threshold audiometry is the basic examination used in the process of diagnosis and follow-up of MD and has a decisive role in treatment decisions. The progressive sensorineural hearing loss, with impairment of low frequencies and the fluctuations, is typical result observed in MD.

The degree of hearing loss seems to be related to the stage of the disease and has a relationship with the symptomatic period. It is common for MD patients a sensorineural hearing loss to moderate to severe before or on the first diagnosis. The settings of the hearing loss may vary; the most common is the ascendant or inverted "U." The flat configuration appears in more advanced stages of the disease. However, different audiometric results can be found and variations in the degree and configuration of hearing loss may be observed, depending on the stage of the disease. Although the low frequencies are generally more affected, hearing loss may be present in all frequencies when in an advanced state of the disease, configuring sometimes an audiogram with flat curve [11]. In this way, the diagnosis of MD should not be established in accordance with the configuration of the audiogram, because there is not a specific audiometric pattern [12]. There is no consensus in the literature that the auditory thresholds for pure tone should be investigated, including thresholds of air and bone conduction and, at least for the frequencies 250 Hz–8 kHz. A difference ≥10 dB is accepted as the float hearing for the MD.

Relationship was found between the occurrence of fluctuation and the severity or progression of the hearing loss. Authors report that the hearing losses affecting the averages (between 500 and 2000 Hz) and high frequencies (between 3000 and 8000 Hz) suggest a worse prognosis than that one affects the low frequencies (between 125 and 500 Hz) [13]. The value of the results of the hearing evaluation by means of ATL has been shown to be significant, and the cochlear symptoms have been described in the literature as the most common initial sign of the disease and, many times, to appear before the vertigo.

The speech perception tests are also compromised. The percentage index of speech recognition (PISR) and the speech recognition threshold (SRT) are altered in MD [12, 13]. The average score of the PISR, when there is hearing loss can be around 56% or less if the MD is of long duration. In cases of unilateral hearing loss, percentages of PISR worst in relation to expected, considering the results of the auditory thresholds for pure tone. The speech in noise tests has helped in the intervention of the patients with MD; individuals with MD unilaterally submitted to simultaneous labyrinthectomy have improvement in sound localization and in speech understanding with and without competitive noise [13]. Acoustic immittance measures course with a type A configuration tympanometry, although in some patients with severe hearing loss of long term may present tympanometry curve characteristic of tubal dysfunction. The acoustic reflex threshold decreases in cochlear pathologies due to recruitment, the difference between the acoustic reflex thresholds of the frequencies of 500, 1000, and 2000 Hz and the tonal auditory thresholds obtained by air, the same frequencies of 60 dB or less, and outcome goal that suggests the presence of cochlear pathology (recruitment) [13]. It is worth mentioning that the acoustic immittance measures can be very useful in the diagnosis of MD, in cases of MD floating and nonfloating and with respect to the prediction of endolymphatic hydrops reversible and irreversible.

Electrocochleography (ECochG) can be used for MD diagnosis. The presence of endolymphatic hydrops is determined by the enlargement of the summation potential (SP) in relation to the action potential (AP), reflecting an increase in relation SP/AP. The SP enlargement is more evident when the patient presents fullness and mild hearing loss. In the initial stages of the MD, the increase in the endolymphatic volume alters the hydromechanical properties of cochlear stretching medium scale and changing SP. The specificity of the relationship SP/AP is larger than the sensitivity in MD. The increase of SP/AP relationship suggests the diagnosis of MD, but only in about 50% of the cases, the disease really exists [13].

#### **4. Available treatments**

The characteristics of the MD are well documented, as well as the treatments for this pathology. The available literature is focused to identify the etiology and how to clinically approach the symptomatic patient. The symptomatic treatment can be pharmacological and/or surgical.

The symptomatic treatment does not prevent the progression of the disease. This treatment may involve diet, vestibular therapy, and drug treatment [11]. In acute vertigo crisis, drugs that block the vestibular reflexes in the vestibule-cerebral shaft can be used. They are chlorpromazine, cinnarizine, promethazine, and diazepam [5, 14].

The endolymphatic hydrops found in MD is treated aiming to prevent its progression. In this way, there is a low sodium diet and use of diuretics, such as furosemide and hydrochlorothiazide [6].

Vasodilators are used for long-term treatment based on the fact that the hydrops can be caused by ischemia of the stria vascularis. Currently, the medical treatment of maintenance is betahistine with or without diuretic [6, 10].

**71**

*The Treatment of Meniere's Disease by the Intratympanic Therapy*

indications for systemic use of aminoglycosides are limited [15].

Studies have shown that the toxic effects of aminoglycosides in the sensorineural

epithelium of the inner ear, particularly in the labyrinth, can be considered as a

In cases of MD with bilateral vestibular symptoms is difficult to control and with important hearing loss, has already been given in the past to ablation of the maze with systemic aminoglycosides because they control the vertigo. However, the cumulative doses of aminoglycosides increase the risk of ototoxicity with permanent cochlear damage and the possibility of causing ataxia and oscillopsia. Currently, with the possibility of injecting substances via transtympanic route, the

In about 70% of the cases, MD evolves to progressive hearing loss with improve-

ment to the vestibular symptoms. For the other 30% who do not present an improvement of vestibular symptoms, even with the clinical treatment, surgical

and it is known as a conservative surgical procedure and is widely accepted.

nal labyrinthectomy, or postauricular labyrinthectomy [4].

The decision to operate and the choice of procedure are often dictated by the understanding and experience of each surgeon [3]. Surgical treatment to be considered varies from conservative to destructive, depending on whether or not there is a hearing loss [3]. The surgery that is the most popular is the endolymphatic sac decompression,

This surgery was first described by Portmann, in 1927, but the precise role by which the surgery works remains undefined [16]. Among the destructive surgical treatments, we have a vestibular neurectomy, the cochleo-sacculotomy, the transca-

The use of systemic aminoglycosides was replaced by intratympanic gentamycin

The intratympanic injections of gentamicin were proposed by Stokroos. After anesthesia of the tympanic membrane, gentamicin is administered in the middle ear through a fine needle of lumbar puncture in a fixed dose of 30 mg/ml [20, 21].

One other substance that can be used is steroid, which may decrease the inflammatory reaction in the inner ear, thus decreasing the endolymphatic hydrops. It has been reported that the use of corticosteroids may help to control the inner ear dysfunction, thereby decreasing vestibular symptoms up to 91% of MD patients (with 1–4 injections of dexamethasone at a concentration of 12 mg/ml) [22, 23]. Another substance to be injected is methylprednisolone, with higher concentrations and with the possibility to last longer in the perilymph. However, many authors described data suggesting same effectiveness of both steroids [24, 25]. Both gentamicin and steroids are absorbed by perilymph through the round window membrane (which is semipermeable), the annular ligament of the oval window, and by the small lacunar mesh that surrounds the inner ear [25].

instillations that are administered once a day by a limited number of days. The intratympanic administration of drugs for the treatment of the MD was primarily described by Schuknecht in 1957 [17]. The intratympanic injections of gentamicin provide a high rate of success in the control of vertigo with reduced number of side

**5. Symptomatic chemical-surgical treatment**

*DOI: http://dx.doi.org/10.5772/intechopen.84752*

therapy for MD [6, 10].

**6. Surgical treatment**

treatment should be thought.

**7. Transtympanic treatment**

effects on hearing [18, 19].

#### **5. Symptomatic chemical-surgical treatment**

Studies have shown that the toxic effects of aminoglycosides in the sensorineural epithelium of the inner ear, particularly in the labyrinth, can be considered as a therapy for MD [6, 10].

In cases of MD with bilateral vestibular symptoms is difficult to control and with important hearing loss, has already been given in the past to ablation of the maze with systemic aminoglycosides because they control the vertigo. However, the cumulative doses of aminoglycosides increase the risk of ototoxicity with permanent cochlear damage and the possibility of causing ataxia and oscillopsia. Currently, with the possibility of injecting substances via transtympanic route, the indications for systemic use of aminoglycosides are limited [15].

#### **6. Surgical treatment**

*Meniere's Disease*

many times, to appear before the vertigo.

Relationship was found between the occurrence of fluctuation and the severity or progression of the hearing loss. Authors report that the hearing losses affecting the averages (between 500 and 2000 Hz) and high frequencies (between 3000 and 8000 Hz) suggest a worse prognosis than that one affects the low frequencies (between 125 and 500 Hz) [13]. The value of the results of the hearing evaluation by means of ATL has been shown to be significant, and the cochlear symptoms have been described in the literature as the most common initial sign of the disease and,

The speech perception tests are also compromised. The percentage index of speech

recognition (PISR) and the speech recognition threshold (SRT) are altered in MD [12, 13]. The average score of the PISR, when there is hearing loss can be around 56% or less if the MD is of long duration. In cases of unilateral hearing loss, percentages of PISR worst in relation to expected, considering the results of the auditory thresholds for pure tone. The speech in noise tests has helped in the intervention of the patients with MD; individuals with MD unilaterally submitted to simultaneous labyrinthectomy have improvement in sound localization and in speech understanding with and without competitive noise [13]. Acoustic immittance measures course with a type A configuration tympanometry, although in some patients with severe hearing loss of long term may present tympanometry curve characteristic of tubal dysfunction. The acoustic reflex threshold decreases in cochlear pathologies due to recruitment, the difference between the acoustic reflex thresholds of the frequencies of 500, 1000, and 2000 Hz and the tonal auditory thresholds obtained by air, the same frequencies of 60 dB or less, and outcome goal that suggests the presence of cochlear pathology (recruitment) [13]. It is worth mentioning that the acoustic immittance measures can be very useful in the diagnosis of MD, in cases of MD floating and nonfloating and with respect to the prediction of endolymphatic hydrops reversible and irreversible. Electrocochleography (ECochG) can be used for MD diagnosis. The presence of endolymphatic hydrops is determined by the enlargement of the summation potential (SP) in relation to the action potential (AP), reflecting an increase in relation SP/AP. The SP enlargement is more evident when the patient presents fullness and mild hearing loss. In the initial stages of the MD, the increase in the endolymphatic volume alters the hydromechanical properties of cochlear stretching medium scale and changing SP. The specificity of the relationship SP/AP is larger than the sensitivity in MD. The increase of SP/AP relationship suggests the diagnosis of MD, but

only in about 50% of the cases, the disease really exists [13].

of maintenance is betahistine with or without diuretic [6, 10].

The characteristics of the MD are well documented, as well as the treatments for this pathology. The available literature is focused to identify the etiology and how to clinically approach the symptomatic patient. The symptomatic treatment can be

The symptomatic treatment does not prevent the progression of the disease. This treatment may involve diet, vestibular therapy, and drug treatment [11]. In acute vertigo crisis, drugs that block the vestibular reflexes in the vestibule-cerebral shaft can be used. They are chlorpromazine, cinnarizine, promethazine, and diazepam [5, 14]. The endolymphatic hydrops found in MD is treated aiming to prevent its progression. In this way, there is a low sodium diet and use of diuretics, such as

Vasodilators are used for long-term treatment based on the fact that the hydrops can be caused by ischemia of the stria vascularis. Currently, the medical treatment

**4. Available treatments**

pharmacological and/or surgical.

furosemide and hydrochlorothiazide [6].

**70**

In about 70% of the cases, MD evolves to progressive hearing loss with improvement to the vestibular symptoms. For the other 30% who do not present an improvement of vestibular symptoms, even with the clinical treatment, surgical treatment should be thought.

The decision to operate and the choice of procedure are often dictated by the understanding and experience of each surgeon [3]. Surgical treatment to be considered varies from conservative to destructive, depending on whether or not there is a hearing loss [3]. The surgery that is the most popular is the endolymphatic sac decompression, and it is known as a conservative surgical procedure and is widely accepted.

This surgery was first described by Portmann, in 1927, but the precise role by which the surgery works remains undefined [16]. Among the destructive surgical treatments, we have a vestibular neurectomy, the cochleo-sacculotomy, the transcanal labyrinthectomy, or postauricular labyrinthectomy [4].

#### **7. Transtympanic treatment**

The use of systemic aminoglycosides was replaced by intratympanic gentamycin instillations that are administered once a day by a limited number of days. The intratympanic administration of drugs for the treatment of the MD was primarily described by Schuknecht in 1957 [17]. The intratympanic injections of gentamicin provide a high rate of success in the control of vertigo with reduced number of side effects on hearing [18, 19].

The intratympanic injections of gentamicin were proposed by Stokroos. After anesthesia of the tympanic membrane, gentamicin is administered in the middle ear through a fine needle of lumbar puncture in a fixed dose of 30 mg/ml [20, 21].

One other substance that can be used is steroid, which may decrease the inflammatory reaction in the inner ear, thus decreasing the endolymphatic hydrops. It has been reported that the use of corticosteroids may help to control the inner ear dysfunction, thereby decreasing vestibular symptoms up to 91% of MD patients (with 1–4 injections of dexamethasone at a concentration of 12 mg/ml) [22, 23].

Another substance to be injected is methylprednisolone, with higher concentrations and with the possibility to last longer in the perilymph. However, many authors described data suggesting same effectiveness of both steroids [24, 25].

Both gentamicin and steroids are absorbed by perilymph through the round window membrane (which is semipermeable), the annular ligament of the oval window, and by the small lacunar mesh that surrounds the inner ear [25].

A randomized, double-blind controlled study compared the use of transtympanic gentamicin (40 mg/ml) and corticosteroids (methylprednisolone [62.5 mg/ml]), and no difference was observed regarding the effectiveness of both groups of treatments [26].

### **8. Injection protocols**


This protocol can be repeated each week or monthly for six times.

To maintain auditory function, patients must be evaluated with tone pure audiometry on every 2 weeks or before beginning each section. The treatment must be stopped in case of hearing thresholds becoming higher than 10 dB or in a case of decreasing in speech audiometry of more than 15%. A supportive drug treatment may be necessary until the vertigo control. A pretreatment auditory test is very important. The bone conduction pure tone thresholds average (0.5, 1.0, 2.0, and 3.0 kHz) is considered and repeated every 2 weeks and 2 weeks after treatment. The final audiometric exam is performed up to 12 months after transtympanic protocol initiation.

The success rate in transtympanic injection of gentamicin is about 87% in vertigo control, being a simple and safe procedure with few risks to hearing loss and tympanic membrane perforation [24, 27].

**73**

**Author details**

São Paulo, Brazil

Maria Stella A. Amaral1

Miguel A. Hyppolito1

provided the original work is properly cited.

\*

Paulo, Riberão Preto, São Paulo, Brazil

\*Address all correspondence to: mahyppo@fmrp.usp.br

*The Treatment of Meniere's Disease by the Intratympanic Therapy*

*DOI: http://dx.doi.org/10.5772/intechopen.84752*

© 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,

2 Department of Health Sciences, Ribeirão Preto Medical School—University of São

, Ana Claudia M.B. Reis2

and

, Henrique F. Pauna1

1 Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeirão Preto Medical School—University of São Paulo, Ribeirão Preto,

### **Acknowledgements**

The authors wish to thank FAEPA and CAPES.

#### **Conflict of interest**

No conflict of interest.

*The Treatment of Meniere's Disease by the Intratympanic Therapy DOI: http://dx.doi.org/10.5772/intechopen.84752*

*Meniere's Disease*

both groups of treatments [26].

1.Patient positioned at supine position;

2.Head is positioned in a slightly hyper-extension with 30o

**8. Injection protocols**

protocol initiation.

**Acknowledgements**

**Conflict of interest**

No conflict of interest.

A randomized, double-blind controlled study compared the use of transtympanic gentamicin (40 mg/ml) and corticosteroids (methylprednisolone [62.5 mg/ml]), and no difference was observed regarding the effectiveness of

3.Instillation 2% lidocaine in ear canal, removing completely after 15 min;

4.Under microscopic examination, tympanic membrane is anesthetized with

5.In few minutes, the transtympanic access could be performed using a spinal

6.Slow instillations of 1 ml of 26–40 mg/ml, not buffered with bicarbonate

To maintain auditory function, patients must be evaluated with tone pure audiometry on every 2 weeks or before beginning each section. The treatment must be stopped in case of hearing thresholds becoming higher than 10 dB or in a case of decreasing in speech audiometry of more than 15%. A supportive drug treatment may be necessary until the vertigo control. A pretreatment auditory test is very important. The bone conduction pure tone thresholds average (0.5, 1.0, 2.0, and 3.0 kHz) is considered and repeated every 2 weeks and 2 weeks after treatment. The final audiometric exam is performed up to 12 months after transtympanic

The success rate in transtympanic injection of gentamicin is about 87% in vertigo control, being a simple and safe procedure with few risks to hearing loss and

needle and a flexible catheter mounted on an insulin syringe;

This protocol can be repeated each week or monthly for six times.

sodium in two 0.5 ml injection with 30 min apart;

7.Patient remained motionless for 30 min.

tympanic membrane perforation [24, 27].

The authors wish to thank FAEPA and CAPES.

80–90% phenol solution at inferior and posterior tympanic membrane quadrant;

contralateral rotation;

**72**

#### **Author details**

Maria Stella A. Amaral1 , Henrique F. Pauna1 , Ana Claudia M.B. Reis2 and Miguel A. Hyppolito1 \*

1 Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeirão Preto Medical School—University of São Paulo, Ribeirão Preto, São Paulo, Brazil

2 Department of Health Sciences, Ribeirão Preto Medical School—University of São Paulo, Riberão Preto, São Paulo, Brazil

\*Address all correspondence to: mahyppo@fmrp.usp.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.

#### **References**

[1] Gürkov R, Pyykö I, Zou J, Kentala E. What is Menière disease? A contemporary re-evaluation of endolymphatic hydrops. Journal of Neurology. 2016;**263**:71-81

[2] Lopez-Escamez JA, Carey J, Chung W-H, et al. Diagnostic criteria for Mennière's disease. Journal of Vestibular Research. 2015;**25**:1-7

[3] Wright T. Menière's disease. BMJ Clinical Evidence. 2015;**11**:505

[4] Saeed SR. Fortnightly review. Diagnosis and treatment of Ménière's disease. British Medical Journal. 1998;**316**(7128):368-372

[5] Salt AN, Plontke SK. Endolymphatic hydrops: Pathophysiology and experimental models. Otolaryngologic Clinics of North America. 2010;**43**(5):971-983

[6] Soderman AC, Bagger-Sjoback D, Bergenius J, Langius A. Factors influencing quality of life in patients with Meniere's disease, identified by a multidimensional approach. Otology & Neurotology. 2002;**23**(6):941-948

[7] Brookes GB. The pharmacological treatment of Menière's disease. Clinical Otolaryngology and Allied Sciences. 1996;**21**(1):3-11. Review

[8] Maudonnet EN, de Oliveira JA, Rossato M, Hyppolito MA. Gentamicin attenuates gentamicin-induced ototoxicity—Self-protection. Drug and Chemical Toxicology. 2008;**31**(1):11-25

[9] Strose A, Hyppolito MA, Colombari GC, Rossato M, Oliveira JA. Lack of protection against gentamicin ototoxicity by auditory conditioning with noise. Brazilian Journal of Otorhinolaryngology. 2014;**80**(5):390-396

[10] Hellström S, Ödkvist L. Pharmacological labyrinthectomy. Otolaryngologic Clinics of North America. 1994;**27**:307-315

[11] Güneri EA, Çakır A, Mutlu B. Validity and reliability of the diagnostic tests for Ménière's disease. Turkish Archives of Otorhinolaryngology. 2016;**54**:124-130

[12] Hoa M, Friedman RA, Fisher LM, Derebery MJ. Prognostic implications of and audiometric evidence for hearing fluctuation in Meniere's disease. The Laryngoscope. 2015;**125**(12):S1-S12

[13] Carey JP. Ménière's disease. Handbook of Clinical Neurophysiology. Elsevier; Baltimore, United States: 2010. pp. 371-381. DOI: 10.1016/ S1567-4231(10)09028-3

[14] Santos PM, Hall RA, Snyder JM, Hughes LF, Dobie RA. Diuretic and diet effect on Menière's disease evaluated by the 1985 Committee on Hearing and Equilibrium guidelines. Otolaryngology and Head and Neck Surgery. 1993;**109**(4):680-689

[15] Nedzelski JM, Schessel DA, Bryce GE, Pheiderer AG. Chemical labyrinthectomy local application of gentamicin for the treatment of unilateral Ménière's disease. The American Journal of Otology. 1992;**13**:18-22

[16] Portmann G. Vertigo: Surgical treatment by opening the saccus endolymphaticus. Archives of Otolaryngology. 1927;**83**:316-319

[17] Beck C. Intratympanic application of gentamicin for treatment of Menière's disease. The Keio Journal of Medicine. 1986;**35**(1):36-41

**75**

*The Treatment of Meniere's Disease by the Intratympanic Therapy*

[26] Patel M, Agarwal K, Arshad Q, et al. Intratympanic methylprednisolone

comparative effectiveness trial. Lancet.

[27] Chia SH, Gamst AC, Anderson JP, et al. Intratympanic gentamicin therapy for Ménière's disease: A metaanalysis. Otology & Neurotology.

versus gentamicin in patients with unilateral Meniere's disease: A randomized, double-blind,

2016;**388**(10061):2753-2762

2004;**25**:544-552

*DOI: http://dx.doi.org/10.5772/intechopen.84752*

meta-analysis. The Laryngoscope.

[19] Diamond C, O'Connell DA, Hornig JD, et al. Systematic review of intratympanic gentamicin in Ménière's disease. The Journal of Otolaryngology.

[20] Stokroos R, Kingma H. Selective vestibular ablation by intratympanic

unilateral active Meniere's disease: A prospective, double-blind, placebocontrolled, randomized clinical trial. Acta Oto-Laryngologica.

[21] Sam G, Chung DW, van der Hoeven R, Verweij S, Becker M. The effect of intratympanic gentamicin for treatment of Ménière's disease on lower frequency hearing. International Journal of Clinical Pharmacy. 2016;**38**(4):780-783. DOI: 10.1007/s11096-016-0295-4

[22] Trune DR, Kempton JB, Kessi M. Aldosterone (mineralocorticoid) equivalent to prednisolone (glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas1pr autoimmune mice. The Laryngoscope.

gentamicin in patients with

2004;**124**(2):172-175

2000;**110**:1902-1906

[23] Boleas-Aguirre MS, Lin FR, Della Santina CC, Minor LB, Carey JP. Longitudinal results with intratympanic dexamethasone in the treatment of Ménière's disease. Otology & Neurotology. 2008;**29**(1):33-38. DOI:

10.1097/mao.0b013e31815dbafc

[25] Patel M. Intratympanic

[24] Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: An animal study followed by clinical application. The Laryngoscope. 1999;**109**(7 Pt 2):1-17

corticosteroids in Ménière's disease: A mini-review. The Journal of Otolaryngology. 2017;**12**(3):117-124. DOI: 10.1016/j.joto.2017.06.002

2004;**114**:2085-2091

2003;**32**:351-361

[18] Cohen-Kerem R, Kisilevsky V, Einarson TR, et al. Intratympanic gentamicin for Ménière's disease: A *The Treatment of Meniere's Disease by the Intratympanic Therapy DOI: http://dx.doi.org/10.5772/intechopen.84752*

meta-analysis. The Laryngoscope. 2004;**114**:2085-2091

[19] Diamond C, O'Connell DA, Hornig JD, et al. Systematic review of intratympanic gentamicin in Ménière's disease. The Journal of Otolaryngology. 2003;**32**:351-361

[20] Stokroos R, Kingma H. Selective vestibular ablation by intratympanic gentamicin in patients with unilateral active Meniere's disease: A prospective, double-blind, placebocontrolled, randomized clinical trial. Acta Oto-Laryngologica. 2004;**124**(2):172-175

[21] Sam G, Chung DW, van der Hoeven R, Verweij S, Becker M. The effect of intratympanic gentamicin for treatment of Ménière's disease on lower frequency hearing. International Journal of Clinical Pharmacy. 2016;**38**(4):780-783. DOI: 10.1007/s11096-016-0295-4

[22] Trune DR, Kempton JB, Kessi M. Aldosterone (mineralocorticoid) equivalent to prednisolone (glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas1pr autoimmune mice. The Laryngoscope. 2000;**110**:1902-1906

[23] Boleas-Aguirre MS, Lin FR, Della Santina CC, Minor LB, Carey JP. Longitudinal results with intratympanic dexamethasone in the treatment of Ménière's disease. Otology & Neurotology. 2008;**29**(1):33-38. DOI: 10.1097/mao.0b013e31815dbafc

[24] Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: An animal study followed by clinical application. The Laryngoscope. 1999;**109**(7 Pt 2):1-17

[25] Patel M. Intratympanic corticosteroids in Ménière's disease: A mini-review. The Journal of Otolaryngology. 2017;**12**(3):117-124. DOI: 10.1016/j.joto.2017.06.002

[26] Patel M, Agarwal K, Arshad Q, et al. Intratympanic methylprednisolone versus gentamicin in patients with unilateral Meniere's disease: A randomized, double-blind, comparative effectiveness trial. Lancet. 2016;**388**(10061):2753-2762

[27] Chia SH, Gamst AC, Anderson JP, et al. Intratympanic gentamicin therapy for Ménière's disease: A metaanalysis. Otology & Neurotology. 2004;**25**:544-552

**74**

*Meniere's Disease*

**References**

[1] Gürkov R, Pyykö I, Zou J, Kentala E.

[10] Hellström S, Ödkvist L. Pharmacological labyrinthectomy. Otolaryngologic Clinics of North

America. 1994;**27**:307-315

2016;**54**:124-130

[11] Güneri EA, Çakır A, Mutlu B. Validity and reliability of the diagnostic tests for Ménière's disease. Turkish Archives of Otorhinolaryngology.

[12] Hoa M, Friedman RA, Fisher LM, Derebery MJ. Prognostic implications of and audiometric evidence for hearing fluctuation in Meniere's disease. The Laryngoscope. 2015;**125**(12):S1-S12

[13] Carey JP. Ménière's disease.

S1567-4231(10)09028-3

and Head and Neck Surgery.

1993;**109**(4):680-689

1992;**13**:18-22

1986;**35**(1):36-41

Handbook of Clinical Neurophysiology. Elsevier; Baltimore, United States: 2010. pp. 371-381. DOI: 10.1016/

[14] Santos PM, Hall RA, Snyder JM, Hughes LF, Dobie RA. Diuretic and diet effect on Menière's disease evaluated by the 1985 Committee on Hearing and Equilibrium guidelines. Otolaryngology

[15] Nedzelski JM, Schessel DA, Bryce GE, Pheiderer AG. Chemical labyrinthectomy local application of gentamicin for the treatment of unilateral Ménière's disease. The American Journal of Otology.

[16] Portmann G. Vertigo: Surgical treatment by opening the saccus endolymphaticus. Archives of Otolaryngology. 1927;**83**:316-319

[17] Beck C. Intratympanic application of gentamicin for treatment of Menière's disease. The Keio Journal of Medicine.

[18] Cohen-Kerem R, Kisilevsky V, Einarson TR, et al. Intratympanic gentamicin for Ménière's disease: A

[2] Lopez-Escamez JA, Carey J, Chung W-H, et al. Diagnostic criteria for Mennière's disease. Journal of Vestibular

[3] Wright T. Menière's disease. BMJ Clinical Evidence. 2015;**11**:505

[4] Saeed SR. Fortnightly review. Diagnosis and treatment of Ménière's disease. British Medical Journal.

hydrops: Pathophysiology and

Clinics of North America. 2010;**43**(5):971-983

[5] Salt AN, Plontke SK. Endolymphatic

experimental models. Otolaryngologic

[6] Soderman AC, Bagger-Sjoback D, Bergenius J, Langius A. Factors influencing quality of life in patients with Meniere's disease, identified by a multidimensional approach. Otology & Neurotology. 2002;**23**(6):941-948

[7] Brookes GB. The pharmacological treatment of Menière's disease. Clinical Otolaryngology and Allied Sciences.

[8] Maudonnet EN, de Oliveira JA, Rossato M, Hyppolito MA. Gentamicin

[9] Strose A, Hyppolito MA, Colombari

gentamicin ototoxicity by auditory conditioning with noise. Brazilian Journal of Otorhinolaryngology.

attenuates gentamicin-induced ototoxicity—Self-protection. Drug and Chemical Toxicology.

GC, Rossato M, Oliveira JA. Lack of protection against

1996;**21**(1):3-11. Review

2008;**31**(1):11-25

2014;**80**(5):390-396

What is Menière disease? A contemporary re-evaluation of endolymphatic hydrops. Journal of

Neurology. 2016;**263**:71-81

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

1998;**316**(7128):368-372

**77**

**1. Introduction**

interventions for most patients.

**Chapter 5**

**Abstract**

Intratympanic Gentamicin

*Yongchuan Chai and Hongzhe Li*

complications, indications, and contraindications.

aminoglycosides, vertigo, vestibulotoxicity, ototoxicity

**Keywords:** intratympanic, gentamicin, Ménière's disease, management,

Ménière's disease (MD), also called idiopathic endolymphatic hydrops, is one of the most common causes of dizziness originating in the inner ear. The typical clinical manifestations are frequent spontaneous vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or aural fullness. Vertigo is typically the most debilitating symptom, and control of vertiginous episodes is the primary goal of therapeutic

There are numerous available therapeutic options for MD including conservative treatments with dietary modifications, oral medication, procedural treatments with intratympanic therapies, and surgical treatments. A failure of conservative therapy often introduces the need for a more aggressive therapy on the treatment algorithm. Surgical intervention or intratympanic aminoglycosides can be used in patients with intractable vertigo, which, ideally, should control the vertigo while preserving the hearing level and balance. The side effects of aminoglycosides are wellknow. The risks of vestibular and cochlear toxicity are mainly related to types of

Treatment for Ménière's Disease

Ménière's disease (MD) is an inner-ear disease mostly characterized by frequent spontaneous vertigo and fluctuating sensorineural hearing loss. The main purpose of treatment for MD is to reduce or control the vertigo while maximizing the preservation of hearing. Among the various treatments, one that is effective for refractory MD, intratympanic gentamicin (ITG), relies on its ototoxic property to effectively control the vertigo symptoms of most patients. ITG treatment has relatively few side effects compared with surgically destructive treatments, but it also carries a nonnegligible risk of sensorineural hearing loss. So far, there is no consensus on the dosage and treatment duration of ITG. Most researchers recommend that intratympanic injection of gentamicin is more suitable for patients with unilateral onset and impaired hearing function, who are younger than 65 years old, as well as with frequent and severe vertigo attacks, and ineffective prior conservative treatment. Before an ITG treatment, patients should be adequately informed about the risk of hearing loss, and in order to reduce the risk of deafness, low drug dose and long intervals between injections are recommended. In short, to administer an ITG injection, multiple factors should be comprehensively considered including patient selection, pharmacological mechanism, drug dose, the interval of administration,

#### **Chapter 5**

## Intratympanic Gentamicin Treatment for Ménière's Disease

*Yongchuan Chai and Hongzhe Li*

#### **Abstract**

Ménière's disease (MD) is an inner-ear disease mostly characterized by frequent spontaneous vertigo and fluctuating sensorineural hearing loss. The main purpose of treatment for MD is to reduce or control the vertigo while maximizing the preservation of hearing. Among the various treatments, one that is effective for refractory MD, intratympanic gentamicin (ITG), relies on its ototoxic property to effectively control the vertigo symptoms of most patients. ITG treatment has relatively few side effects compared with surgically destructive treatments, but it also carries a nonnegligible risk of sensorineural hearing loss. So far, there is no consensus on the dosage and treatment duration of ITG. Most researchers recommend that intratympanic injection of gentamicin is more suitable for patients with unilateral onset and impaired hearing function, who are younger than 65 years old, as well as with frequent and severe vertigo attacks, and ineffective prior conservative treatment. Before an ITG treatment, patients should be adequately informed about the risk of hearing loss, and in order to reduce the risk of deafness, low drug dose and long intervals between injections are recommended. In short, to administer an ITG injection, multiple factors should be comprehensively considered including patient selection, pharmacological mechanism, drug dose, the interval of administration, complications, indications, and contraindications.

**Keywords:** intratympanic, gentamicin, Ménière's disease, management, aminoglycosides, vertigo, vestibulotoxicity, ototoxicity

#### **1. Introduction**

Ménière's disease (MD), also called idiopathic endolymphatic hydrops, is one of the most common causes of dizziness originating in the inner ear. The typical clinical manifestations are frequent spontaneous vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or aural fullness. Vertigo is typically the most debilitating symptom, and control of vertiginous episodes is the primary goal of therapeutic interventions for most patients.

There are numerous available therapeutic options for MD including conservative treatments with dietary modifications, oral medication, procedural treatments with intratympanic therapies, and surgical treatments. A failure of conservative therapy often introduces the need for a more aggressive therapy on the treatment algorithm.

Surgical intervention or intratympanic aminoglycosides can be used in patients with intractable vertigo, which, ideally, should control the vertigo while preserving the hearing level and balance. The side effects of aminoglycosides are wellknow. The risks of vestibular and cochlear toxicity are mainly related to types of

aminoglycosides, route of administration, duration of the therapy, total or cumulative dose, individual susceptibility, renal function, patient's age, etc.

In 1948, Fowler [1] first used systemic streptomycin to treat vertigo attacks in patients with intractable MD. The results showed that vertigo attacks could be well controlled, but treatment carried the risks of bilateral vestibulopathy, nephrotoxicity, and unpredictable results. In 1957, Schuknekt [2] may have been the first to use intratympanic streptomycin to alleviate vertigo attacks in patients with unilateral intractable MD, and it was firstly named "chemical labyrinthectomy". Intratympanic gentamicin (ITG) for the treatment of severe vertigo was reported by Lange [3]. The initial approach was complete vestibular ablation to control the vertigo. However, with this approach, the hearing was at a greater risk. Over the past decades, the pharmacological mechanisms of aminoglycosides have been progressively studied in depth and clinical trials have been extensively developed.

At present, intratympanic injection of gentamicin is probably the most effective non-surgical treatment to eradicate vertigo in MD and is gradually gaining popularity in the worldwide. Compared with the treatment regimen decades ago, several modifications for ITG treatment have emerged regarding the concentration of the gentamicin solution, the frequency of injections, and the method of delivery. In this chapter, the history, background, and progression of ITG treatment for MD are discussed, as well as the basic science, therapeutic method, treatment efficacy, indications, contraindications, and complications.

#### **2. History of intratympanic gentamicin**

Aminoglycosides are highly potent, broad-spectrum antibiotics and are widely used by various routes of injection to treat serious infections caused by Gram-negative bacteria (e.g., *Pseudomonas aeruginosa*, *Proteus* species, *Escherichia coli*, *Klebsiella-Enterobacter-Serratia* species, and *Citrobacter* species), and are sometimes used as an adjuvant treatment for infections caused by Gram-positive bacteria (e.g., *Staphylococcus* species). The basic chemical structure required for both potency and the spectrum of antimicrobial activity of aminoglycosides is that of one, or several, aminated sugars joined in glycosidic linkages to a dibasic cyclitol. Aminoglycosides act primarily by impairing bacterial protein synthesis through binding to prokaryotic ribosomes [4].

Streptomycin, which was discovered in 1944, is the first aminoglycoside antibiotic in human history and was thereafter marked by the successive introduction of a series of milestone compounds (kanamycin discovered in 1957, gentamicin in 1963, and neomycin in 1970s) which definitively established the usefulness of this class of antibiotics for the treatment of Gram-negative bacillary infections. From the 1960s to 1970s, aminoglycosides were widely used, but due to their serious ototoxicity and nephrotoxicity, their systemic application was limited, and they were gradually fading out of the ranks of first-line drugs. At the beginning, the most common side effect of streptomycin used by intravenous injection was temporary imbalance without vertigo or nystagmus. Higher systemic doses increased the chance of permanent imbalance and, occasionally, deafness. These early observations led to animal and cadaver studies which confirmed the vestibulotoxic and cochleotoxic effects of high-dose streptomycin.

Based on its vestibulotoxicity, streptomycin foremost unveiled its potential in the treatment of vestibular diseases. In 1948, about 4 years after streptomycin was discovered, Fowler [1] first used systemic streptomycin to treat vertigo attacks in patients with intractable MD which was refractory to traditional medical treatment. He and others used between 2 and 4 g of intramuscular streptomycin per day in patients with unilateral or bilateral MD, typically until onset of severe imbalance,

**79**

reduction of cochleotoxicity.

*Intratympanic Gentamicin Treatment for Ménière's Disease*

and reported that vertigo attacks could be well controlled without loss of hearing. Often, and especially with higher dosing, vertigo control was accompanied with the

In 1957, Schuknecht [2] may have been the first to use intratympanic streptomycin to alleviate vertigo attacks in patients with unilateral MD that was uncontrolled by traditional medical management. He conceived of this idea after noting that intratympanic formalin will readily pass into the inner ear and prevented postmortem degeneration of the inner ear membranous structures in patients. He correctly theorized that streptomycin could also pass into the inner ear and devised a cat animal model that demonstrated clinical and pathologic vestibulotoxicity with intratympanic streptomycin. Based on these results, he devised a clinical trial of intratympanic streptomycin administration to patients with uncontrolled unilateral MD. He administered variable amounts of streptomycin (between 0.125 and 0.5 g), either hourly or over 4 hours, over a variable amount of days. The first group of three patients who received 1 or 2 days of treatment achieved only brief control of their vertigo, but did not lose any hearing. Subsequently, an additional group of five patients received streptomycin for 3 days or longer. These patients had permanent resolution of their vertigo episodes, but at the cost of deafening the ear. Schuknekt coined the term "chemical labyrinthectomy" to describe this phenomenon. He concluded that intratympanic streptomycin at the therapeutic dosage failed to preserve hearing, and should only be considered for patients who are not good surgical candidates, but would otherwise be proper candidates for inner ear ablation [2]. With the administration of intratympanic aminoglycosides, chemical ablation of the inner ear via systemic administration of aminoglycosides fell into disfavor due to the side effects of bilateral vestibulopathy, nephrotoxicity, and unpredictable results. However, choosing which kind of aminoglycoside for intratympanic injection has gradually changed. In 1977, Lange [3] appears to be the first to have used IT administration of gentamicin. He reported about 55 patients suffering from severe unilateral MD, seen over a period of 3–10 years. Patients were treated with intratympanic administration of streptomycin or better, gentamicin. The medication was given using a plastic tube inserted behind the annulus within the transmeatal approach, and 0.1 ml gentamicin (earlier streptomycin) was instilled every 5 hours until the first signs of inner ear reaction (nystagmus or vertigo) appeared. In 90% of the cases, vertiginous attacks ceased after therapy, and hearing was preserved in 76%. Entering the 1990s, intratympanic gentamicin had gained widespread popularity in the treatment of MD. Compared with streptomycin, ITG for treatment of MD provided equivalently excellent vertigo control while showing a lower incidence of hearing loss in early clinical data. Gentamicin gained popularity over streptomycin and gradually came to be the drug of choice for chemical ablation of inner ear.

In 1993, Nedzelski et al. [5] studied 50 patients with unilateral MD by treatment of microcatheter administration of streptomycin over a 5 h treatment, 4 treatments within 48 hours, and the rate of vertigo control was up to 96%; only 24% of his patients experienced various degrees of hearing loss. Although streptomycin was being used in the study, he advocated for using gentamicin instead for its theoretical

Beck and Schmidt [6] reported on their 10 years of experience with intratympanally applied streptomycin and gentamicin in the therapy of MD. They theorized that the dosage might be a critical factor for hearing preservation with vertigo control. Aminoglycosides could be titrated to impede the secretory epithelium of the vestibular apparatus without destroying the sensory cells, thus achieving vertigo control while maintaining caloric response, that is, vestibulo-ocular reflex. More importantly, risk of deafness could potentially be eliminated. By reducing the dosage delivered and titrating, they were able to achieve excellent rates of vertigo

troubling symptoms of permanent, severe imbalance, and oscillopsia.

*DOI: http://dx.doi.org/10.5772/intechopen.86790*

#### *Intratympanic Gentamicin Treatment for Ménière's Disease DOI: http://dx.doi.org/10.5772/intechopen.86790*

*Meniere's Disease*

aminoglycosides, route of administration, duration of the therapy, total or cumula-

In 1948, Fowler [1] first used systemic streptomycin to treat vertigo attacks in patients with intractable MD. The results showed that vertigo attacks could be well controlled, but treatment carried the risks of bilateral vestibulopathy, nephrotoxicity, and unpredictable results. In 1957, Schuknekt [2] may have been the first to use intratympanic streptomycin to alleviate vertigo attacks in patients with unilateral intractable MD, and it was firstly named "chemical labyrinthectomy". Intratympanic gentamicin (ITG) for the treatment of severe vertigo was reported by Lange [3]. The initial approach was complete vestibular ablation to control the vertigo. However, with this approach, the hearing was at a greater risk. Over the past decades, the pharmacological mechanisms of aminoglycosides have been progressively studied in depth and clinical trials have been extensively developed. At present, intratympanic injection of gentamicin is probably the most effective non-surgical treatment to eradicate vertigo in MD and is gradually gaining popularity in the worldwide. Compared with the treatment regimen decades ago, several modifications for ITG treatment have emerged regarding the concentration of the gentamicin solution, the frequency of injections, and the method of delivery. In this chapter, the history, background, and progression of ITG treatment for MD are discussed, as well as the basic science, therapeutic method, treatment efficacy,

Aminoglycosides are highly potent, broad-spectrum antibiotics and are widely used by various routes of injection to treat serious infections caused by Gram-negative bacteria (e.g., *Pseudomonas aeruginosa*, *Proteus* species, *Escherichia coli*, *Klebsiella-Enterobacter-Serratia* species, and *Citrobacter* species), and are sometimes used as an adjuvant treatment for infections caused by Gram-positive bacteria (e.g., *Staphylococcus* species). The basic chemical structure required for both potency and the spectrum of antimicrobial activity of aminoglycosides is that of one, or several, aminated sugars joined in glycosidic linkages to a dibasic cyclitol. Aminoglycosides act primarily by impairing bacterial protein synthesis through binding to prokaryotic ribosomes [4]. Streptomycin, which was discovered in 1944, is the first aminoglycoside antibiotic in human history and was thereafter marked by the successive introduction of a series of milestone compounds (kanamycin discovered in 1957, gentamicin in 1963, and neomycin in 1970s) which definitively established the usefulness of this class of antibiotics for the treatment of Gram-negative bacillary infections. From the 1960s to 1970s, aminoglycosides were widely used, but due to their serious ototoxicity and nephrotoxicity, their systemic application was limited, and they were gradually fading out of the ranks of first-line drugs. At the beginning, the most common side effect of streptomycin used by intravenous injection was temporary imbalance without vertigo or nystagmus. Higher systemic doses increased the chance of permanent imbalance and, occasionally, deafness. These early observations led to animal and cadaver studies which confirmed the vestibulotoxic and cochleotoxic

Based on its vestibulotoxicity, streptomycin foremost unveiled its potential in the treatment of vestibular diseases. In 1948, about 4 years after streptomycin was discovered, Fowler [1] first used systemic streptomycin to treat vertigo attacks in patients with intractable MD which was refractory to traditional medical treatment. He and others used between 2 and 4 g of intramuscular streptomycin per day in patients with unilateral or bilateral MD, typically until onset of severe imbalance,

tive dose, individual susceptibility, renal function, patient's age, etc.

indications, contraindications, and complications.

**2. History of intratympanic gentamicin**

effects of high-dose streptomycin.

**78**

and reported that vertigo attacks could be well controlled without loss of hearing. Often, and especially with higher dosing, vertigo control was accompanied with the troubling symptoms of permanent, severe imbalance, and oscillopsia.

In 1957, Schuknecht [2] may have been the first to use intratympanic streptomycin to alleviate vertigo attacks in patients with unilateral MD that was uncontrolled by traditional medical management. He conceived of this idea after noting that intratympanic formalin will readily pass into the inner ear and prevented postmortem degeneration of the inner ear membranous structures in patients. He correctly theorized that streptomycin could also pass into the inner ear and devised a cat animal model that demonstrated clinical and pathologic vestibulotoxicity with intratympanic streptomycin. Based on these results, he devised a clinical trial of intratympanic streptomycin administration to patients with uncontrolled unilateral MD. He administered variable amounts of streptomycin (between 0.125 and 0.5 g), either hourly or over 4 hours, over a variable amount of days. The first group of three patients who received 1 or 2 days of treatment achieved only brief control of their vertigo, but did not lose any hearing. Subsequently, an additional group of five patients received streptomycin for 3 days or longer. These patients had permanent resolution of their vertigo episodes, but at the cost of deafening the ear. Schuknekt coined the term "chemical labyrinthectomy" to describe this phenomenon. He concluded that intratympanic streptomycin at the therapeutic dosage failed to preserve hearing, and should only be considered for patients who are not good surgical candidates, but would otherwise be proper candidates for inner ear ablation [2].

With the administration of intratympanic aminoglycosides, chemical ablation of the inner ear via systemic administration of aminoglycosides fell into disfavor due to the side effects of bilateral vestibulopathy, nephrotoxicity, and unpredictable results. However, choosing which kind of aminoglycoside for intratympanic injection has gradually changed. In 1977, Lange [3] appears to be the first to have used IT administration of gentamicin. He reported about 55 patients suffering from severe unilateral MD, seen over a period of 3–10 years. Patients were treated with intratympanic administration of streptomycin or better, gentamicin. The medication was given using a plastic tube inserted behind the annulus within the transmeatal approach, and 0.1 ml gentamicin (earlier streptomycin) was instilled every 5 hours until the first signs of inner ear reaction (nystagmus or vertigo) appeared. In 90% of the cases, vertiginous attacks ceased after therapy, and hearing was preserved in 76%.

Entering the 1990s, intratympanic gentamicin had gained widespread popularity in the treatment of MD. Compared with streptomycin, ITG for treatment of MD provided equivalently excellent vertigo control while showing a lower incidence of hearing loss in early clinical data. Gentamicin gained popularity over streptomycin and gradually came to be the drug of choice for chemical ablation of inner ear.

In 1993, Nedzelski et al. [5] studied 50 patients with unilateral MD by treatment of microcatheter administration of streptomycin over a 5 h treatment, 4 treatments within 48 hours, and the rate of vertigo control was up to 96%; only 24% of his patients experienced various degrees of hearing loss. Although streptomycin was being used in the study, he advocated for using gentamicin instead for its theoretical reduction of cochleotoxicity.

Beck and Schmidt [6] reported on their 10 years of experience with intratympanally applied streptomycin and gentamicin in the therapy of MD. They theorized that the dosage might be a critical factor for hearing preservation with vertigo control. Aminoglycosides could be titrated to impede the secretory epithelium of the vestibular apparatus without destroying the sensory cells, thus achieving vertigo control while maintaining caloric response, that is, vestibulo-ocular reflex. More importantly, risk of deafness could potentially be eliminated. By reducing the dosage delivered and titrating, they were able to achieve excellent rates of vertigo

control (92%) while also achieving respectable hearing preservation rates (15% hearing loss with no cases of deafness).

During the same era, around the early 1990s, two schools of thought emerged in an effort to standardize ITG treatment, dubbed the "shotgun" approach, and the "low-dose" approach. The shotgun approach, championed by Nedzelski and others [5], was characterized by daily IT injections to a fixed endpoint or to a clinical threshold that heralded damage to the inner ear. Proponents of this approach attempted to achieve adequate vestibular ablation for long-term vertigo control. The low-dose approach, championed by Magnusson and others [7], was characterized by weekly IT injections, also to a fixed endpoint or to clinical effect. Proponents of this approach tried to achieve vertigo control while minimizing damage to hearing and potentially preserving the caloric response as well.

Today, intratympanic injection of gentamicin is probably the most effective nonsurgical treatment to eradicate vertigo in MD. Yet, it is an ablative method that carries a non-negligible risk of hearing loss. Currently, gentamicin is usually instilled via IT injection or through a tympanostomy tube to the round window niche. These injections are repeated over a variable amount of time, typically between daily to weekly injections, until a clinical endpoint is achieved or until there is a decline in hearing. No consensus has been reached so far on the overall dosage, dosing methods, timing of delivery, treatment duration, clinical endpoint of therapy, or concentration of gentamicin. Both clinical evidence and basic science models should be further studied to scientifically elicit the most effective and safe regimen.

#### **3. Mechanism of action**

Aminoglycoside antibiotics have a well-documented history of cochleotoxic and vestibulotoxic effects. Administration of intratympanic aminoglycoside antibiotics to patients with MD is based on the notion that the patient's vestibular symptoms are due to the damaged and distorted vestibular signals emanating from their ear and that they are better off with no signal than with a damaged and distorted signal. The objective of ITG is to weaken vestibular signals in the Ménière's ear to the point at which they are no longer strong enough to generate a vertigo attack. Ideally, aminoglycosides would act to reduce vestibular function, and thus alleviate the patient's symptoms of vertigo, while preserving hearing. The degree to which a drug is cochleotoxic or vestibulotoxic differs among aminoglycosides. Gentamicin and streptomycin, for instance, are reported to be more vestibulotoxic. Other aminoglycosides, such as amikacin, are considered to be relatively more cochleotoxic and thus are not used transtympanically. The best evidence for this is the simple clinical observation that patients undergoing systemic gentamicin or streptomycin therapy experience vestibulopathy much more commonly than hearing loss. This feature has been used by otologists to control the vestibular symptoms of MD, initially provided through systemic delivery by Fowler [1] and subsequently through IT injections by Schuknecht [2, 8]. Use of streptomycin has been largely replaced by gentamicin which is thought to be more selectively vestibulotoxic and better able to preserve residual hearing in patients with unilateral MD refractory to medical management [9, 10].

Within the bony labyrinth, several studies have investigated the trafficking and distribution of aminoglycosides, finding different patterns of distribution dependent upon the dose, duration, and route of administration. IT-injected aminoglycosides appear to gain access to the inner ear via the oval window and the round window [11, 12], and uptake either by passive diffusion or by endocytosis [13, 14]. Salt et al. recently quantified diffusion of gentamicin through the oval (35%)

**81**

administration.

maculae [28].

while preserving cochlear function.

*Intratympanic Gentamicin Treatment for Ménière's Disease*

transport of aminoglycosides into cells of the inner ear [19].

cochlear duct, and vestibule and then exerts its cellular toxicity.

versus the round window (57%) [12, 15]. Access to these membranous structures is however uncertain, partly due to their variable permeability in individuals, resulting in unpredictable drug exposure of the inner ear [16–18]. Similar mechanisms of cellular trafficking (active diffusion and endocytosis) have been proposed in the

Once the drug crosses the oval window and the round window, the situation becomes more complex and the precise mechanism by which aminoglycosides exert their toxic effects on hair cells is unknown, to date. Previous animal studies showed that in the cochlea, sensory hair cells, the spiral ligament including the stria vascularis, and spiral ganglion cells had a very early uptake of gentamicin. Similarly, hair cells, dark cells, and vestibular ganglion cells are the primary targets in the vestibular system. This may demonstrate that gentamicin most likely diffuses across the inner ear membranes, readily achieving concentrations within the scala vestibuli,

Multiple mechanisms, including disruption of calcium-dependent cytokine production resulting in the damage to hair cell membrane integrity, increased superoxide production, hair cell transduction blockage, glutamate decarboxylase inhibition, ornithine decarboxylase inhibition, and free radical damage, all have been developed to explain aminoglycosides' direct toxicity to hair cells [10, 20, 21]. While most cells of the inner ear demonstrate aminoglycoside penetration, several studies have identified preferential loss of the hair cells at the basal turn of the cochlea over the apical hair cells and vestibular type I hair cells over their type II counterparts [22–26]. Direct damage to the spiral ganglion has also been observed [27] and histologic studies in rhesus monkeys suggest relative sparing of the

In parallel to previous findings, several studies have demonstrated that direct application of gentamicin into the vestibular labyrinth also causes greater loss of type I versus type II vestibular hair cells [29, 30]. Recently, Lyford-Pike et al. [26] used the animal model, chinchilla, to provide the evidence that the selective loss of type I hair cells assuredly occurred because these cells preferentially accumulate gentamicin acutely after intratympanic administration. Type II hair cells and supporting cells concentrate substantially less gentamicin. These results might theoretically ameliorate the more profound symptom of vertigo (driven by type I hair cells)

Aminoglycosides may also act to inhibit production of endolymph, restoring the balance between endolymphatic and perilymphatic pressure. This would also act to alleviate all symptoms of endolymphatic hydrops. Additionally, aminoglycosides are theorized to cause selective damage to the cells of the cochlear stria vascularis and planum semilunatum in the cristae ampullae of the semicircular canals, which are involved in ionic regulation and endolymph production [31]. It is also known that gentamicin utilizes the cellular machinery of endolymph production to traffic into the inner ear after systemic administration [32]. The theory that vestibular dark cells and, thus, endolymphatic flow, are the targets by which aminoglycosides alleviate vertigo is of significant clinical interest because it suggests that it is not necessarily important to ablate the vestibule to achieve vertigo control in MD. This idea can explain why patients with intact caloric responses can still achieve significant vertigo control after intratympanic aminoglycoside

In conclusion, direct toxicity to vestibular hair cells and direct toxicity to the endolymph producing apparatus might be the two major mechanisms of action by ITG. Most importantly, gentamicin has been proved to be more vestibulotoxic than cochleotoxic in humans. The inner ear toxicity of gentamicin might follow an order. Secretory dark cells of the vestibule might be the first to be damaged, followed by

*DOI: http://dx.doi.org/10.5772/intechopen.86790*

*Meniere's Disease*

hearing loss with no cases of deafness).

**3. Mechanism of action**

and potentially preserving the caloric response as well.

control (92%) while also achieving respectable hearing preservation rates (15%

During the same era, around the early 1990s, two schools of thought emerged in an effort to standardize ITG treatment, dubbed the "shotgun" approach, and the "low-dose" approach. The shotgun approach, championed by Nedzelski and others [5], was characterized by daily IT injections to a fixed endpoint or to a clinical threshold that heralded damage to the inner ear. Proponents of this approach attempted to achieve adequate vestibular ablation for long-term vertigo control. The low-dose approach, championed by Magnusson and others [7], was characterized by weekly IT injections, also to a fixed endpoint or to clinical effect. Proponents of this approach tried to achieve vertigo control while minimizing damage to hearing

Today, intratympanic injection of gentamicin is probably the most effective nonsurgical treatment to eradicate vertigo in MD. Yet, it is an ablative method that carries a non-negligible risk of hearing loss. Currently, gentamicin is usually instilled via IT injection or through a tympanostomy tube to the round window niche. These injections are repeated over a variable amount of time, typically between daily to weekly injections, until a clinical endpoint is achieved or until there is a decline in hearing. No consensus has been reached so far on the overall dosage, dosing methods, timing of delivery, treatment duration, clinical endpoint of therapy, or concentration of gentamicin. Both clinical evidence and basic science models should be

Aminoglycoside antibiotics have a well-documented history of cochleotoxic and vestibulotoxic effects. Administration of intratympanic aminoglycoside antibiotics to patients with MD is based on the notion that the patient's vestibular symptoms are due to the damaged and distorted vestibular signals emanating from their ear and that they are better off with no signal than with a damaged and distorted signal. The objective of ITG is to weaken vestibular signals in the Ménière's ear to the point at which they are no longer strong enough to generate a vertigo attack. Ideally, aminoglycosides would act to reduce vestibular function, and thus alleviate the patient's symptoms of vertigo, while preserving hearing. The degree to which a drug is cochleotoxic or vestibulotoxic differs among aminoglycosides. Gentamicin and streptomycin, for instance, are reported to be more vestibulotoxic. Other aminoglycosides, such as amikacin, are considered to be relatively more cochleotoxic and thus are not used transtympanically. The best evidence for this is the simple clinical observation that patients undergoing systemic gentamicin or streptomycin therapy experience vestibulopathy much more commonly than hearing loss. This feature has been used by otologists to control the vestibular symptoms of MD, initially provided through systemic delivery by Fowler [1] and subsequently through IT injections by Schuknecht [2, 8]. Use of streptomycin has been largely replaced by gentamicin which is thought to be more selectively vestibulotoxic and better able to preserve residual hearing in patients with unilateral MD refractory to medical

Within the bony labyrinth, several studies have investigated the trafficking and distribution of aminoglycosides, finding different patterns of distribution dependent upon the dose, duration, and route of administration. IT-injected aminoglycosides appear to gain access to the inner ear via the oval window and the round window [11, 12], and uptake either by passive diffusion or by endocytosis [13, 14]. Salt et al. recently quantified diffusion of gentamicin through the oval (35%)

further studied to scientifically elicit the most effective and safe regimen.

**80**

management [9, 10].

versus the round window (57%) [12, 15]. Access to these membranous structures is however uncertain, partly due to their variable permeability in individuals, resulting in unpredictable drug exposure of the inner ear [16–18]. Similar mechanisms of cellular trafficking (active diffusion and endocytosis) have been proposed in the transport of aminoglycosides into cells of the inner ear [19].

Once the drug crosses the oval window and the round window, the situation becomes more complex and the precise mechanism by which aminoglycosides exert their toxic effects on hair cells is unknown, to date. Previous animal studies showed that in the cochlea, sensory hair cells, the spiral ligament including the stria vascularis, and spiral ganglion cells had a very early uptake of gentamicin. Similarly, hair cells, dark cells, and vestibular ganglion cells are the primary targets in the vestibular system. This may demonstrate that gentamicin most likely diffuses across the inner ear membranes, readily achieving concentrations within the scala vestibuli, cochlear duct, and vestibule and then exerts its cellular toxicity.

Multiple mechanisms, including disruption of calcium-dependent cytokine production resulting in the damage to hair cell membrane integrity, increased superoxide production, hair cell transduction blockage, glutamate decarboxylase inhibition, ornithine decarboxylase inhibition, and free radical damage, all have been developed to explain aminoglycosides' direct toxicity to hair cells [10, 20, 21]. While most cells of the inner ear demonstrate aminoglycoside penetration, several studies have identified preferential loss of the hair cells at the basal turn of the cochlea over the apical hair cells and vestibular type I hair cells over their type II counterparts [22–26]. Direct damage to the spiral ganglion has also been observed [27] and histologic studies in rhesus monkeys suggest relative sparing of the maculae [28].

In parallel to previous findings, several studies have demonstrated that direct application of gentamicin into the vestibular labyrinth also causes greater loss of type I versus type II vestibular hair cells [29, 30]. Recently, Lyford-Pike et al. [26] used the animal model, chinchilla, to provide the evidence that the selective loss of type I hair cells assuredly occurred because these cells preferentially accumulate gentamicin acutely after intratympanic administration. Type II hair cells and supporting cells concentrate substantially less gentamicin. These results might theoretically ameliorate the more profound symptom of vertigo (driven by type I hair cells) while preserving cochlear function.

Aminoglycosides may also act to inhibit production of endolymph, restoring the balance between endolymphatic and perilymphatic pressure. This would also act to alleviate all symptoms of endolymphatic hydrops. Additionally, aminoglycosides are theorized to cause selective damage to the cells of the cochlear stria vascularis and planum semilunatum in the cristae ampullae of the semicircular canals, which are involved in ionic regulation and endolymph production [31]. It is also known that gentamicin utilizes the cellular machinery of endolymph production to traffic into the inner ear after systemic administration [32]. The theory that vestibular dark cells and, thus, endolymphatic flow, are the targets by which aminoglycosides alleviate vertigo is of significant clinical interest because it suggests that it is not necessarily important to ablate the vestibule to achieve vertigo control in MD. This idea can explain why patients with intact caloric responses can still achieve significant vertigo control after intratympanic aminoglycoside administration.

In conclusion, direct toxicity to vestibular hair cells and direct toxicity to the endolymph producing apparatus might be the two major mechanisms of action by ITG. Most importantly, gentamicin has been proved to be more vestibulotoxic than cochleotoxic in humans. The inner ear toxicity of gentamicin might follow an order. Secretory dark cells of the vestibule might be the first to be damaged, followed by

the vestibular neuroepithelium and the afferent vestibular fibers, and finally, the hair cells of the organ of Corti are destroyed [33, 34].

#### **4. Therapeutic method and treatment efficacy**

Ménière's disease is manifested by episodic vertigo, tinnitus, aural fullness, and fluctuating hearing loss. The treatment of patients with MD is usually directed at the most disabling symptom, which is the debilitating vertigo. MD treatment protocols typically measure vertigo control according to AAO-HNS Committee on Hearing and Equilibrium guidelines for grading vertigo severity [35]. Often, clinical trials also attempt to assess other disease sequelae such as hearing loss, tinnitus, and aural fullness.

As a well-known relapsing-remitting disease, it is rather difficult to accurately evaluate the efficacy of ITG in treatment of MD. Firstly, the natural history of remission and exacerbation of symptoms make evaluation of the effectiveness of treatment remarkably difficult. Commonly, vertigo attacks can improve without treatment of any kind as periods of remission are not uncommon. Thus, a clinical trial without controls will not account for this finding. Another difficulty is that clinical researchers attempt to show hearing preservation with IT gentamicin protocol, but hearing tends to worsen over time in MD regardless of treatment. Finally, the variable nature of MD with fluctuation in levels of hearing and even frequency and severity of vertigo can make clinical trials difficult.

To date, there have only been a few interventional randomized controlled trials investigating the true efficacy of ITG in the treatment of MD. In 2004, the first prospective, double-blind, randomized clinical trial of intratympanic gentamicin versus intratympanic buffer solution (placebo) in patients with active MD was reported by Stokroos et al. [36]. They performed ITG injections with buffered gentamicin (30 mg/ml) every 6 weeks until the vertigo complaints disappeared (12 patients received gentamicin versus 10 for placebo), outcome measures included the number of vertiginous spells, degree of sensorineural hearing loss, labyrinthine function, and labyrinthine asymmetry. Compared to the placebo group, topical gentamicin provided a significant improvement in the number of vertiginous attacks per year at follow up which varied between 6 and 28 months. There was no statistically significant change in hearing or other outcomes in two groups. However, hearing had a tendency to deteriorate in the placebo-treated patients, due to the natural course of the disease, which suggests that early treatment with topical gentamicin may preserve residual sensorineural hearing in active MD.

In 2008, Postema et al. [37] reported another prospective, double-blind, randomized, placebo-controlled trial associated with ITG therapy for control of vertigo in unilateral MD. They used weekly injections of 0.4 ml of gentamicin (30 mg/ml). A total of 4 injections were given through a ventilation tube (16 patients received gentamicin and 12 received a placebo). The results showed that gentamicin treatment resulted in a significant reduction of the score for vertigo complaints (including vertigo severity) and the score for perceived aural fullness. They also noted that a small increase in hearing loss (average of losses at 0.5, 1, 2, and 4 kHz: 8 dB HL) was measured in the gentamicin group.

In 2016, Patel et al. [38] performed a randomized, double-blind, comparative effectiveness trial of intratympanic methylprednisolone (n = 30) versus gentamicin (n = 30) in patients with refractory unilateral MD. Patients were randomly assigned (1:1) to two intratympanic methylprednisolone (62.5 mg/ml) or gentamicin (40 mg/ml) injections given 2 weeks apart, and were followed up for 2 years. In the methylprednisolone group, complete vertigo control (Class A) was achieved in 21/30 patients

**83**

*Intratympanic Gentamicin Treatment for Ménière's Disease*

93.4% of vertigo control and 25.6% of hearing loss.

2 injections of gentamicin and 81% vertigo control.

In the early 2000s, regarding patients with hearing deterioration and even those becoming deaf, there was a discussion about reducing the gentamicin dose or performing the application at longer intervals. Daily titration methods were abandoned. Transtympanic gentamicin therapy was modified to weekly or monthly intervals as "needed" or "on demand" to reduce the symptoms of MD, aiming to maintain cochlear as well as vestibular function. Harner et al. [45] reported a very high rate of vertigo control with preservation of hearing in 43 patients. There were no patients with changes in cochlear function and ablation of the labyrinth. All patients received one injection, and half of them received a repeat injection 1 month after therapy. Minor [46] used gentamicin on weekly intervals until the development of spontaneous nystagmus, head-shaking nystagmus, or head thrust sign. Vertigo was controlled in 91% of the patients, and profound hearing loss only occurred in 1 patient. Atlas and Parnes [47] reviewed the outcomes of 83 patients who received weekly injections. They reported hearing loss in 17% of the patients, with vertigo control in 84%. Martin and Perez [48] reported vertigo control in 83.1% of the patients and hearing loss in 15.5% of them after gentamicin at weekly intervals. De Beer et al. [49] reported 15.8% with hearing loss and 80.7% with vertigo control after, between 1 and 10, intratympanic injections at a minimum interval of 27 days. Casani et al. [50] reported 12% hearing loss after a maximum of

(70%) compared to 25/30 (83.3%) in the gentamicin group. After methylprednisolone, 22 patients (78.5%) experienced an improved functional level score and 8 patients (28.7%) better pure-tone hearing and speech discrimination. There were also reductions for tinnitus, dizziness, and aural fullness. Fifteen patients (50%) required further courses of methylprednisolone. Two patients were deemed treatment failures and were assigned ITG treatment. The study showed no significant difference between the methylprednisolone and gentamicin for the control of vertigo, total number of injections, number of patients with relapsing vertigo, or the amount of pain from injection but better speech discrimination after methylprednisolone. Based on the above prospective, double-blind, randomized controlled clinical trials, intratympanic gentamicin, as a medically ablative method, seems to be the most effective non-surgical treatment to eradicate vertigo in intractable MD, but with a potential risk of hearing loss. However, there is no consensus on the treatment protocol of ITG, especially for the concentration of gentamicin, dosage in each application, number of injection, and the time interval between two doses. In the over 40 years of clinical trials in the treatment of MD by ITG, the majority are case series without controls, mainly because of the significant difficulties in conducting the randomized controlled clinical trials or case/control trials [33]. In earlier studies, the highest rate of vertigo control was reported with daily injections or multiple titrations. On the other hand, considerable hearing loss was experienced in several studies. Moller et al. [39] treated 15 patients with disabling MD with daily injections for periods ranging from 3 to 11 days. They achieved 93.4% of vertigo control, but also 33.4% of hearing loss. They reported that none of the patients were responsive to caloric stimulation. Laitakari [40] reported 90% of vertigo control and 45% of hearing loss in 20 patients who had daily ITG for a minimum of 3 consecutive days. Parnes and Riddell [41] reported 41.7% worsening of the hearing in their group of patients who received three daily injections within 4 days. Murofushi et al. [42], using several daily injections, reported hearing loss in 30% of cases. Corsten et al. [43] reported 81% vertigo control but 57% hearing loss in patients (n = 21) who had gentamicin instillation 3 times a day for 4 consecutive days. Kaplan et al. [44] reviewed the 10-year long-term results of 114 patients treated with gentamicin instillation 3 times a day for 4 consecutive days. They achieved

*DOI: http://dx.doi.org/10.5772/intechopen.86790*

#### *Intratympanic Gentamicin Treatment for Ménière's Disease DOI: http://dx.doi.org/10.5772/intechopen.86790*

*Meniere's Disease*

aural fullness.

the vestibular neuroepithelium and the afferent vestibular fibers, and finally, the

Ménière's disease is manifested by episodic vertigo, tinnitus, aural fullness, and fluctuating hearing loss. The treatment of patients with MD is usually directed at the most disabling symptom, which is the debilitating vertigo. MD treatment protocols typically measure vertigo control according to AAO-HNS Committee on Hearing and Equilibrium guidelines for grading vertigo severity [35]. Often, clinical trials also attempt to assess other disease sequelae such as hearing loss, tinnitus, and

As a well-known relapsing-remitting disease, it is rather difficult to accurately evaluate the efficacy of ITG in treatment of MD. Firstly, the natural history of remission and exacerbation of symptoms make evaluation of the effectiveness of treatment remarkably difficult. Commonly, vertigo attacks can improve without treatment of any kind as periods of remission are not uncommon. Thus, a clinical trial without controls will not account for this finding. Another difficulty is that clinical researchers attempt to show hearing preservation with IT gentamicin protocol, but hearing tends to worsen over time in MD regardless of treatment. Finally, the variable nature of MD with fluctuation in levels of hearing and even frequency

To date, there have only been a few interventional randomized controlled trials investigating the true efficacy of ITG in the treatment of MD. In 2004, the first prospective, double-blind, randomized clinical trial of intratympanic gentamicin versus intratympanic buffer solution (placebo) in patients with active MD was reported by Stokroos et al. [36]. They performed ITG injections with buffered gentamicin (30 mg/ml) every 6 weeks until the vertigo complaints disappeared (12 patients received gentamicin versus 10 for placebo), outcome measures included the number of vertiginous spells, degree of sensorineural hearing loss, labyrinthine function, and labyrinthine asymmetry. Compared to the placebo group, topical gentamicin provided a significant improvement in the number of vertiginous attacks per year at follow up which varied between 6 and 28 months. There was no statistically significant change in hearing or other outcomes in two groups. However, hearing had a tendency to deteriorate in the placebo-treated patients, due to the natural course of the disease, which suggests that early treatment with topical

hair cells of the organ of Corti are destroyed [33, 34].

**4. Therapeutic method and treatment efficacy**

and severity of vertigo can make clinical trials difficult.

gentamicin may preserve residual sensorineural hearing in active MD.

was measured in the gentamicin group.

In 2008, Postema et al. [37] reported another prospective, double-blind, randomized, placebo-controlled trial associated with ITG therapy for control of vertigo in unilateral MD. They used weekly injections of 0.4 ml of gentamicin (30 mg/ml). A total of 4 injections were given through a ventilation tube (16 patients received gentamicin and 12 received a placebo). The results showed that gentamicin treatment resulted in a significant reduction of the score for vertigo complaints (including vertigo severity) and the score for perceived aural fullness. They also noted that a small increase in hearing loss (average of losses at 0.5, 1, 2, and 4 kHz: 8 dB HL)

In 2016, Patel et al. [38] performed a randomized, double-blind, comparative effectiveness trial of intratympanic methylprednisolone (n = 30) versus gentamicin (n = 30) in patients with refractory unilateral MD. Patients were randomly assigned (1:1) to two intratympanic methylprednisolone (62.5 mg/ml) or gentamicin (40 mg/ml) injections given 2 weeks apart, and were followed up for 2 years. In the methylprednisolone group, complete vertigo control (Class A) was achieved in 21/30 patients

**82**

(70%) compared to 25/30 (83.3%) in the gentamicin group. After methylprednisolone, 22 patients (78.5%) experienced an improved functional level score and 8 patients (28.7%) better pure-tone hearing and speech discrimination. There were also reductions for tinnitus, dizziness, and aural fullness. Fifteen patients (50%) required further courses of methylprednisolone. Two patients were deemed treatment failures and were assigned ITG treatment. The study showed no significant difference between the methylprednisolone and gentamicin for the control of vertigo, total number of injections, number of patients with relapsing vertigo, or the amount of pain from injection but better speech discrimination after methylprednisolone.

Based on the above prospective, double-blind, randomized controlled clinical trials, intratympanic gentamicin, as a medically ablative method, seems to be the most effective non-surgical treatment to eradicate vertigo in intractable MD, but with a potential risk of hearing loss. However, there is no consensus on the treatment protocol of ITG, especially for the concentration of gentamicin, dosage in each application, number of injection, and the time interval between two doses.

In the over 40 years of clinical trials in the treatment of MD by ITG, the majority are case series without controls, mainly because of the significant difficulties in conducting the randomized controlled clinical trials or case/control trials [33]. In earlier studies, the highest rate of vertigo control was reported with daily injections or multiple titrations. On the other hand, considerable hearing loss was experienced in several studies. Moller et al. [39] treated 15 patients with disabling MD with daily injections for periods ranging from 3 to 11 days. They achieved 93.4% of vertigo control, but also 33.4% of hearing loss. They reported that none of the patients were responsive to caloric stimulation. Laitakari [40] reported 90% of vertigo control and 45% of hearing loss in 20 patients who had daily ITG for a minimum of 3 consecutive days. Parnes and Riddell [41] reported 41.7% worsening of the hearing in their group of patients who received three daily injections within 4 days. Murofushi et al. [42], using several daily injections, reported hearing loss in 30% of cases. Corsten et al. [43] reported 81% vertigo control but 57% hearing loss in patients (n = 21) who had gentamicin instillation 3 times a day for 4 consecutive days. Kaplan et al. [44] reviewed the 10-year long-term results of 114 patients treated with gentamicin instillation 3 times a day for 4 consecutive days. They achieved 93.4% of vertigo control and 25.6% of hearing loss.

In the early 2000s, regarding patients with hearing deterioration and even those becoming deaf, there was a discussion about reducing the gentamicin dose or performing the application at longer intervals. Daily titration methods were abandoned. Transtympanic gentamicin therapy was modified to weekly or monthly intervals as "needed" or "on demand" to reduce the symptoms of MD, aiming to maintain cochlear as well as vestibular function. Harner et al. [45] reported a very high rate of vertigo control with preservation of hearing in 43 patients. There were no patients with changes in cochlear function and ablation of the labyrinth. All patients received one injection, and half of them received a repeat injection 1 month after therapy. Minor [46] used gentamicin on weekly intervals until the development of spontaneous nystagmus, head-shaking nystagmus, or head thrust sign. Vertigo was controlled in 91% of the patients, and profound hearing loss only occurred in 1 patient. Atlas and Parnes [47] reviewed the outcomes of 83 patients who received weekly injections. They reported hearing loss in 17% of the patients, with vertigo control in 84%. Martin and Perez [48] reported vertigo control in 83.1% of the patients and hearing loss in 15.5% of them after gentamicin at weekly intervals. De Beer et al. [49] reported 15.8% with hearing loss and 80.7% with vertigo control after, between 1 and 10, intratympanic injections at a minimum interval of 27 days. Casani et al. [50] reported 12% hearing loss after a maximum of 2 injections of gentamicin and 81% vertigo control.

Most recently, Vlastarakos et al. [51] published a systematic review looking at sustained-release delivery of IT gentamicin (dynamic-release versus sustainedrelease vehicles). Dynamic release (microcatheter at the round window) was found to provide satisfactory vertigo control in 89.3% (70.9% reporting complete control). Sustained-release preparations (gentamicin-soaked wick/pledget) provided 82.2% satisfactory control in the pool of patients (75% with complete control). In patients receiving sustained-release preparations, complete hearing loss was reported in 31.1% patients with another 23.3% of patients experiencing partial hearing loss. This adverse change in hearing was unacceptably high, reinforcing the suggestion of using a sustained-release vehicle only in patients who had failed IT gentamicin injections previously or those without serviceable hearing.

Commonly, intratympanic injection under otoscope or microscope is a simple and recommendable technique. The desired amount of gentamicin is injected over the round window through the posterosuperior quadrant of the tympanic membrane. There are two common doses of gentamicin for injection. The standard intravenous preparation of gentamicin is 40 mg/ml, which can be buffered with 8.4% sodium bicarbonate so that discomfort on injection is reduced. A total of 1.5 ml of gentamicin mixed with 0.5 ml of sodium bicarbonate at these concentrations will produce a final concentration of 26.6 mg/ml gentamicin. Approximately 0.3–0.5 ml of solution is usually adequate to bathe the round window in solution. Typically, patients will remain lying flat with the injected ear up for 10 min to 1 h. This procedure is generally well tolerated by patients, who should be told to expect brief pain on injection, followed by possible vertigo or disequilibrium. Warming the medication can help in this regard (preventing a cold caloric response).

Based on the combination of current clinical practice, basic science models, and results from clinical trials, low drug dose and long interval between injections, mainly in order to reduce the risk of deafness, are reasonably encouraged. The low dose method involves using 1–2 injections of gentamicin and waiting a month or 2 weeks between injections. The rate of vertigo control may be up to 80–90%, with no significant side effects. The second injection is given only if there has been a vertigo spell 2 weeks prior. In other words, instead of titrating to the onset of damage to the vestibular system, the criterion is a positive effect on the disease. Occasionally, a third dose is given.

In short, whatever technique is used, the goal is to apply gentamicin to the round window in sufficient concentration and over a sufficient amount of time that it achieves a therapeutic effect while avoiding both local and systemic side effects, especially hearing loss.

#### **5. Indications and contraindications**

Not all patients with MD can be treated with ITG. Based on the international consensus on treatment of MD obtained from the IFOS meeting 2017 [52], MD should be treated with a step-by-step therapy. The first line of treatment includes the medical conservative treatment, such as dietary modification and oral medicine. After this line of treatment, 80% of patients with MD are cured or in remission. When the vertigo of MD fails to be controlled by the first-line treatment for more than 6 months, it will be regarded as intractable MD. Then the second line is the IT injections, mainly IT steroids as a conservative treatment and ITG in the case of IT steroid failure, and preferentially in patients with hearing impairment. After the second line treatment, 90–95% of the total

**85**

injection.

*Intratympanic Gentamicin Treatment for Ménière's Disease*

patients are cured or in remission. The third line is the surgical, either conservative or destructive, treatment. For unilateral intractable MD with serviceable hearing (i.e., speech reception threshold better than 50 dB HL and speech discrimination score of more than 50%) in the treated ear, treatment protocol with an injection repetition not shorter than 1 week between adjacent injections or one with injections on a monthly basis as "needed" is preferred. These methods provide the same level of vertigo control yet offer better preservation of hearing

The best indication for ITG treatment appears to be the control of vertigo in profound hearing loss or non-serviceable ears, in which speech reception threshold is worse than 50 dB HL and speech discrimination score less than 50% [53, 54]. Under these scenarios, there is no need to consider the risk of deafness, and titration methods or multiple injections on a daily basis are preferred, since these methods have significantly elevated incidence of hearing loss [33]. Transmastoid labyrinthectomy has traditionally been offered for non-serviceable ears in patients with MD. This method has been the gold standard, and it is very effective in eradication of vertigo in more than 94% of patients. In comparison, ITG therapy provides a minimally invasive ambulatory substitute with low morbidity and fewer side-effects, which is also very cost effective to manage vertigo in these MD

Another important indicator is the control of vertigo in patients who have failed endolymphatic sac surgery. Marzo and Leonetti [55] have shown the effectiveness of ITG therapy for patients who have failed endolymphatic sac surgery, thus reduc-

To be allergic and hypersensitive to aminoglycosides are two absolute contraindications for ITG. It is worth noting that patients who carried the mitochondrial mutation of the gene MT-RNR1 (mitochondrially encoded 12S ribosomal RNA) are hypersensitive to aminoglycosides. A single injection of aminoglycosides results in complete and definitive deafness in subjects with this mutation [56]. A systematic genetic screening of MD patients is highly recommended to prevent the occurrence of bilateral deafness. The treatment is intended for the abolition of vestibular function; thus, administration of gentamicin must be done carefully in the elderly, who have difficulty attaining vestibular compensation, in patients with complications, or in those with bilateral MD. Taking also into consideration the fact that individual's drug sensitivity depends on their genetic background, investigation of appropriate drug levels according to evidence-based medicine

The complications of ITG treatment are primarily bi-fold: one is the risk caused by drug toxicity of gentamicin, the other is the risk caused by intratympanic injection. Undoubtedly, the main risk of ITG treatment for vertigo is the sensorineural hearing loss and associated prolonged disequilibrium and ataxia, which are common complaints after this treatment. Less common side effects include local hemorrhage, allergic response and tympanic membrane perforation (especially in an irradiated or otherwise damaged tympanic membrane), local discomfort, inflammation, otitis media or externa, and transient vertigo caused by a caloric reflex effect from the instilled fluid [38, 57]. It is also critical to educate all patients who are given intratympanic aminoglycosides that bilateral permanent hearing loss is possible, even from one single unilateral

ing the need for vestibular neurectomy in those with intractable disease.

*DOI: http://dx.doi.org/10.5772/intechopen.86790*

patients with non-serviceable ears [53].

remains a future task.

**6. Complications**

functions [33].

*Meniere's Disease*

hearing.

response).

third dose is given.

especially hearing loss.

**5. Indications and contraindications**

Most recently, Vlastarakos et al. [51] published a systematic review looking at sustained-release delivery of IT gentamicin (dynamic-release versus sustainedrelease vehicles). Dynamic release (microcatheter at the round window) was found to provide satisfactory vertigo control in 89.3% (70.9% reporting complete control). Sustained-release preparations (gentamicin-soaked wick/pledget) provided 82.2% satisfactory control in the pool of patients (75% with complete control). In patients receiving sustained-release preparations, complete hearing loss was reported in 31.1% patients with another 23.3% of patients experiencing partial hearing loss. This adverse change in hearing was unacceptably high, reinforcing the suggestion of using a sustained-release vehicle only in patients who had failed IT gentamicin injections previously or those without serviceable

Commonly, intratympanic injection under otoscope or microscope is a simple and recommendable technique. The desired amount of gentamicin is injected over the round window through the posterosuperior quadrant of the tympanic membrane. There are two common doses of gentamicin for injection. The standard intravenous preparation of gentamicin is 40 mg/ml, which can be buffered with 8.4% sodium bicarbonate so that discomfort on injection is reduced. A total of 1.5 ml of gentamicin mixed with 0.5 ml of sodium bicarbonate at these concentrations will produce a final concentration of 26.6 mg/ml gentamicin. Approximately 0.3–0.5 ml of solution is usually adequate to bathe the round window in solution. Typically, patients will remain lying flat with the injected ear up for 10 min to 1 h. This procedure is generally well tolerated by patients, who should be told to expect brief pain on injection, followed by possible vertigo or disequilibrium. Warming the medication can help in this regard (preventing a cold caloric

Based on the combination of current clinical practice, basic science models, and results from clinical trials, low drug dose and long interval between injections, mainly in order to reduce the risk of deafness, are reasonably encouraged. The low dose method involves using 1–2 injections of gentamicin and waiting a month or 2 weeks between injections. The rate of vertigo control may be up to 80–90%, with no significant side effects. The second injection is given only if there has been a vertigo spell 2 weeks prior. In other words, instead of titrating to the onset of damage to the vestibular system, the criterion is a positive effect on the disease. Occasionally, a

In short, whatever technique is used, the goal is to apply gentamicin to the round

Not all patients with MD can be treated with ITG. Based on the international

consensus on treatment of MD obtained from the IFOS meeting 2017 [52], MD should be treated with a step-by-step therapy. The first line of treatment includes the medical conservative treatment, such as dietary modification and oral medicine. After this line of treatment, 80% of patients with MD are cured or in remission. When the vertigo of MD fails to be controlled by the first-line treatment for more than 6 months, it will be regarded as intractable MD. Then the second line is the IT injections, mainly IT steroids as a conservative treatment and ITG in the case of IT steroid failure, and preferentially in patients with hearing impairment. After the second line treatment, 90–95% of the total

window in sufficient concentration and over a sufficient amount of time that it achieves a therapeutic effect while avoiding both local and systemic side effects,

**84**

patients are cured or in remission. The third line is the surgical, either conservative or destructive, treatment. For unilateral intractable MD with serviceable hearing (i.e., speech reception threshold better than 50 dB HL and speech discrimination score of more than 50%) in the treated ear, treatment protocol with an injection repetition not shorter than 1 week between adjacent injections or one with injections on a monthly basis as "needed" is preferred. These methods provide the same level of vertigo control yet offer better preservation of hearing functions [33].

The best indication for ITG treatment appears to be the control of vertigo in profound hearing loss or non-serviceable ears, in which speech reception threshold is worse than 50 dB HL and speech discrimination score less than 50% [53, 54]. Under these scenarios, there is no need to consider the risk of deafness, and titration methods or multiple injections on a daily basis are preferred, since these methods have significantly elevated incidence of hearing loss [33]. Transmastoid labyrinthectomy has traditionally been offered for non-serviceable ears in patients with MD. This method has been the gold standard, and it is very effective in eradication of vertigo in more than 94% of patients. In comparison, ITG therapy provides a minimally invasive ambulatory substitute with low morbidity and fewer side-effects, which is also very cost effective to manage vertigo in these MD patients with non-serviceable ears [53].

Another important indicator is the control of vertigo in patients who have failed endolymphatic sac surgery. Marzo and Leonetti [55] have shown the effectiveness of ITG therapy for patients who have failed endolymphatic sac surgery, thus reducing the need for vestibular neurectomy in those with intractable disease.

To be allergic and hypersensitive to aminoglycosides are two absolute contraindications for ITG. It is worth noting that patients who carried the mitochondrial mutation of the gene MT-RNR1 (mitochondrially encoded 12S ribosomal RNA) are hypersensitive to aminoglycosides. A single injection of aminoglycosides results in complete and definitive deafness in subjects with this mutation [56]. A systematic genetic screening of MD patients is highly recommended to prevent the occurrence of bilateral deafness. The treatment is intended for the abolition of vestibular function; thus, administration of gentamicin must be done carefully in the elderly, who have difficulty attaining vestibular compensation, in patients with complications, or in those with bilateral MD. Taking also into consideration the fact that individual's drug sensitivity depends on their genetic background, investigation of appropriate drug levels according to evidence-based medicine remains a future task.

#### **6. Complications**

The complications of ITG treatment are primarily bi-fold: one is the risk caused by drug toxicity of gentamicin, the other is the risk caused by intratympanic injection. Undoubtedly, the main risk of ITG treatment for vertigo is the sensorineural hearing loss and associated prolonged disequilibrium and ataxia, which are common complaints after this treatment. Less common side effects include local hemorrhage, allergic response and tympanic membrane perforation (especially in an irradiated or otherwise damaged tympanic membrane), local discomfort, inflammation, otitis media or externa, and transient vertigo caused by a caloric reflex effect from the instilled fluid [38, 57]. It is also critical to educate all patients who are given intratympanic aminoglycosides that bilateral permanent hearing loss is possible, even from one single unilateral injection.

### **7. Conclusions**

Intratympanic injection of gentamicin is probably the most effective nonsurgical treatment to eradicate vertigo in MD. But it is also an ablative method that carries a non-negligible risk of hearing loss. Gentamicin has been proved to be more vestibulotoxic than cochleotoxic; direct toxicity to vestibular hair cells and direct toxicity to the endolymph producing apparatus might be the two major mechanisms of action. To date, no consensus has been reached on the dosage, dosing methods, timing of delivery, treatment duration, clinical endpoint of therapy, and concentration of gentamicin. However, based on the combination of current clinical practice, basic science models, and results from clinical trials, low drug dose and long intervals between injections are reasonably recommended. The application of gentamicin-induced vestibular ablation has minimized the number of more invasive procedures such as unilateral labyrinthectomy and vestibular neurectomy. In comparison with surgery, the vertigo control is comparable, the overall cost is reduced, and complications are limited. ITG in treating intractable MD has gradually become a prevalent therapy during the past decades. However, to administer ITG treatment, multiple factors should be comprehensively considered including patient selection, pharmacological mechanism, drug dose, the interval of administration, complications, indications, and contraindications.

### **Acknowledgements**

The authors thank Alisa Hetrick for her comments on an earlier version of the article.

**87**

**Author details**

United States

Shanghai, China

China

Yongchuan Chai1,2,3,4,5 and Hongzhe Li1,2,6\*

School of Medicine, Loma Linda, CA, United States

provided the original work is properly cited.

1 Research Service, VA Loma Linda Healthcare System, Loma Linda, CA,

2 Loma Linda University School of Medicine, Loma Linda, CA, United States

3 Department of Otorhinolaryngology—Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai,

4 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

6 Department of Otolaryngology—Head and Neck Surgery, Loma Linda University

© 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,

\*Address all correspondence to: hongzhe.li@va.gov; hongzhe@gmail.com

5 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases,

*Intratympanic Gentamicin Treatment for Ménière's Disease*

*DOI: http://dx.doi.org/10.5772/intechopen.86790*

### **Conflict of interest**

The authors declare no competing financial interest.

### **Author details**

*Meniere's Disease*

**7. Conclusions**

tions, indications, and contraindications.

The authors declare no competing financial interest.

**Acknowledgements**

**Conflict of interest**

article.

Intratympanic injection of gentamicin is probably the most effective nonsurgical treatment to eradicate vertigo in MD. But it is also an ablative method that carries a non-negligible risk of hearing loss. Gentamicin has been proved to be more vestibulotoxic than cochleotoxic; direct toxicity to vestibular hair cells and direct toxicity to the endolymph producing apparatus might be the two major mechanisms of action. To date, no consensus has been reached on the dosage, dosing methods, timing of delivery, treatment duration, clinical endpoint of therapy, and concentration of gentamicin. However, based on the combination of current clinical practice, basic science models, and results from clinical trials, low drug dose and long intervals between injections are reasonably recommended. The application of gentamicin-induced vestibular ablation has minimized the number of more invasive procedures such as unilateral labyrinthectomy and vestibular neurectomy. In comparison with surgery, the vertigo control is comparable, the overall cost is reduced, and complications are limited. ITG in treating intractable MD has gradually become a prevalent therapy during the past decades. However, to administer ITG treatment, multiple factors should be comprehensively considered including patient selection, pharmacological mechanism, drug dose, the interval of administration, complica-

The authors thank Alisa Hetrick for her comments on an earlier version of the

**86**

Yongchuan Chai1,2,3,4,5 and Hongzhe Li1,2,6\*

1 Research Service, VA Loma Linda Healthcare System, Loma Linda, CA, United States

2 Loma Linda University School of Medicine, Loma Linda, CA, United States

3 Department of Otorhinolaryngology—Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

4 Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

5 Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China

6 Department of Otolaryngology—Head and Neck Surgery, Loma Linda University School of Medicine, Loma Linda, CA, United States

\*Address all correspondence to: hongzhe.li@va.gov; hongzhe@gmail.com

© 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.

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[2] Schuknecht HF. Ablation therapy in the management of Meniere's disease. Acta Oto-Laryngologica. Supplementum. 1957;**132**:1-42

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[6] Beck C, Schmidt CL. 10 years of experience with intratympanally applied streptomycin (gentamycin) in the therapy of Morbus Meniere. Archives of Oto-Rhino-Laryngology. 1978;**221**:149-152

[7] Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Meniere's disease. Rationale for extremely low dose therapy. Acta Oto-Laryngologica. 1991;**111**:671-676

[8] Schuknecht HF. Ablation therapy for the relief of Meniere's disease. Laryngoscope. 1956;**66**:859-870

[9] Webster JC, McGee TM, Carroll R, Benitez JT, Williams ML. Ototoxicity

of gentamicin. Histopathologic and functional results in the cat. Transactions of the American Academy of Ophthalmology and Otolaryngology. 1970;**74**:1155-1165

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[15] Salt AN, Ma Y. Quantification of solute entry into cochlear perilymph through the round window membrane. Hearing Research. 2001;**154**:88-97

[16] Silverstein H, Rowan PT, Olds MJ, Rosenberg SI. Inner ear perfusion and the role of round window patency. The American Journal of Otology. 1997;**18**:586-589

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Kim JR. Secondary apoptosis of spiral ganglion cells induced by aminoglycoside: Fas–Fas ligand signaling pathway. The Laryngoscope.

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Neuroscience. 1997;**15**:447-461

Quantification of the process of hair cell loss and recovery in the chinchilla crista ampullaris after gentamicin treatment. International Journal of Developmental

[30] Hirvonen TP, Minor LB, Hullar TE, Carey JP. Effects of intratympanic gentamicin on vestibular afferents and hair cells in the chinchilla. Journal of Neurophysiology. 2005;**93**:643-655

[31] Atlas J, Parnes LS. Intratympanic gentamicin for intractable Meniere's disease: 5-year follow-up. The Journal of

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Otolaryngology. 2003;**32**:288-293

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2008;**118**:1659-1668

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Nakashima T. Individual differences in the permeability of the round window: Evaluating the movement of intratympanic gadolinium into the inner ear. Otology and Neurotology.

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[19] Carey J. Intratympanic gentamicin for the treatment of Meniere's disease and other forms of peripheral vertigo. Otolaryngologic Clinics of North America. 2004;**37**:1075-1090

and plugs: Possible effect on

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[21] Schacht J. Biochemical basis of aminoglycoside ototoxicity. Otolaryngologic Clinics of North America. 1993;**26**:845-856

1969;**119**:410-416

[22] Wersall J, Lundquist PG, Bjorkroth B. Ototoxicity of gentamicin. The Journal of Infectious Diseases.

[23] Lindeman HH. Regional differences in sensitivity of the vestibular sensory epithelia to ototoxic antibiotics. Acta Oto-Laryngologica. 1969;**67**:177-189

[24] de Groot JC, Meeuwsen F, Ruizendaal WE, Veldman JE. Ultrastructural localization of gentamicin in the cochlea. Hearing

[25] Tsuji K, Velazquez-Villasenor L, Rauch SD, Glynn RJ, Wall C, Merchant SN. Temporal bone studies of the human peripheral vestibular system. Aminoglycoside ototoxicity. The Annals of Otology, Rhinology and Laryngology

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Nakashima T. Individual differences in the permeability of the round window: Evaluating the movement of intratympanic gadolinium into the inner ear. Otology and Neurotology. 2009;**30**:645-648

[18] Alzamil KS, Linthicum FH Jr. Extraneous round window membranes and plugs: Possible effect on intratympanic therapy. The Annals of Otology, Rhinology, and Laryngology. 2000;**109**:30-32

[19] Carey J. Intratympanic gentamicin for the treatment of Meniere's disease and other forms of peripheral vertigo. Otolaryngologic Clinics of North America. 2004;**37**:1075-1090

[20] Williams SE, Zenner HP, Schacht J. Three molecular steps of aminoglycoside ototoxicity demonstrated in outer hair cells. Hearing Research. 1987;**30**:11-18

[21] Schacht J. Biochemical basis of aminoglycoside ototoxicity. Otolaryngologic Clinics of North America. 1993;**26**:845-856

[22] Wersall J, Lundquist PG, Bjorkroth B. Ototoxicity of gentamicin. The Journal of Infectious Diseases. 1969;**119**:410-416

[23] Lindeman HH. Regional differences in sensitivity of the vestibular sensory epithelia to ototoxic antibiotics. Acta Oto-Laryngologica. 1969;**67**:177-189

[24] de Groot JC, Meeuwsen F, Ruizendaal WE, Veldman JE. Ultrastructural localization of gentamicin in the cochlea. Hearing Research. 1990;**50**:35-42

[25] Tsuji K, Velazquez-Villasenor L, Rauch SD, Glynn RJ, Wall C, Merchant SN. Temporal bone studies of the human peripheral vestibular system. Aminoglycoside ototoxicity. The Annals of Otology, Rhinology and Laryngology Supplement. 2000;**181**:20-25

[26] Lyford-Pike S, Vogelheim C, Chu E, Della Santina CC, Carey JP. Gentamicin is primarily localized in vestibular type I hair cells after intratympanic administration. Journal of the Association for Research in Otolaryngology: JARO. 2007;**8**:497-508

[27] Bae WY, Kim LS, Hur DY, Jeong SW, Kim JR. Secondary apoptosis of spiral ganglion cells induced by aminoglycoside: Fas–Fas ligand signaling pathway. The Laryngoscope. 2008;**118**:1659-1668

[28] Sun DQ, Lehar M, Dai C, Swarthout L, Lauer AM, Carey JP, et al. Histopathologic changes of the inner ear in Rhesus monkeys after intratympanic gentamicin injection and vestibular prosthesis electrode array implantation. Journal of the Association for Research in Otolaryngology: JARO. 2015;**16**:373-387

[29] Lopez I, Honrubia V, Lee SC, Schoeman G, Beykirch K. Quantification of the process of hair cell loss and recovery in the chinchilla crista ampullaris after gentamicin treatment. International Journal of Developmental Neuroscience. 1997;**15**:447-461

[30] Hirvonen TP, Minor LB, Hullar TE, Carey JP. Effects of intratympanic gentamicin on vestibular afferents and hair cells in the chinchilla. Journal of Neurophysiology. 2005;**93**:643-655

[31] Atlas J, Parnes LS. Intratympanic gentamicin for intractable Meniere's disease: 5-year follow-up. The Journal of Otolaryngology. 2003;**32**:288-293

[32] Li H, Steyger PS. Systemic aminoglycosides are trafficked via endolymph into cochlear hair cells. Scientific Reports. 2011;**1**:159

[33] Yetiser S. Intratympanic gentamicin for intractable Meniere's disease—A review and analysis of audiovestibular impact. International Archives of Otorhinolaryngology. 2018;**22**:190-194

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*Meniere's Disease*

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[1] Fowler EP Jr. Streptomycin treatment of vertigo. Transactions of the American of gentamicin. Histopathologic and functional results in the cat. Transactions of the American Academy of Ophthalmology and Otolaryngology.

[10] Rudnick MD, Ginsberg IA, Huber PS. Aminoglycoside ototoxicity following middle ear injection. The Annals of Otology, Rhinology and Laryngology. Supplement. 1980;**89**:i-iii, 1-28

[11] Smith BM, Myers MG. The penetration of gentamicin and neomycin into perilymph across the round window membrane. Otolaryngology—Head and Neck

[12] Salt AN, Hartsock JJ, Gill RM, King E, Kraus FB, Plontke SK. Perilymph pharmacokinetics of locally-applied gentamicin in the guinea pig. Hearing

[13] Goycoolea MV. Clinical aspects of round window membrane permeability

Michaelides EM, Kartush JM, Zappia JJ,

[15] Salt AN, Ma Y. Quantification of solute entry into cochlear perilymph through the round window membrane. Hearing Research. 2001;**154**:88-97

[16] Silverstein H, Rowan PT, Olds MJ, Rosenberg SI. Inner ear perfusion and the role of round window patency. The American Journal of Otology.

[17] Yoshioka M, Naganawa S, Sone M, Nakata S, Teranishi M,

Surgery. 1979;**87**:888-891

Research. 2016;**342**:101-111

under normal and pathological conditions. Acta Oto-Laryngologica.

[14] Becvarovski Z, Bojrab DI,

LaRouere MJ. Round window gentamicin absorption: An in vivo human model. The Laryngoscope.

2001;**121**:437-447

2002;**112**:1610-1613

1997;**18**:586-589

1970;**74**:1155-1165

Academy of Ophthalmology and Otolaryngology. 1948;**52**:293-301

[3] Lange G. The intratympanic treatment of Meniere's disease with ototoxic antibiotics. A follow-up study of 55 cases (author's transl). Laryngologie, Rhinologie, Otologie.

[4] Mingeot-Leclercq MP, Glupczynski Y, Tulkens PM. Aminoglycosides: Activity and resistance. Antimicrobial

[5] Nedzelski JM, Chiong CM, Fradet G, Schessel DA, Bryce GE, Pfleiderer AG. Intratympanic gentamicin instillation as treatment of unilateral Meniere's disease: Update of an ongoing study. The American Journal of Otology.

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Agents and Chemotherapy.

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**93**

Section 5

Surgical Treatment
