Teamwork Approach to Hearing Loss in Children

**45**

**Chapter 4**

**Abstract**

Neonatal Hearing Screening

*Gaston Eduardo Estudillo Jiménez, Edgar Flores Molina* 

Around the world 10 million people have some type or degree of auditory problem, of them, between 200,000 and 400,000 have total deafness. Estimating that a large population presents this problem from birth (61%), with an incidence of 1 to 3 of every 1000 newborns. For this reason, early implementation through the neonatal auditory sieve allows timely detection to respond early to the hearing impairment of the newborn, as the ideal age to carry out rehabilitation with the help of an auditory auxiliary and initiate Language therapy is at six months of age. Most of the international guides for the integral attention to persons with auditory disability it indicates that all newborns should be screened Auditory before his hospital discharge. The prevalence of auditory disturbances in our environment is 0.3%, a proportion that places us above national and global statistics, so it is very important to screen all newborns including those who do not have Apparent risk factors in order to establish the appropriate diagnosis, the necessary treatment and

Hearing loss is the most common neurosensory alteration in the human being, due to the loss or alteration of the anatomical and/or physiological function of the auditory system [1]. It is estimated that worldwide 1 out of every 1000 children is born with bilateral hearing loss. To the deep and 5 out of every 1000 with other forms of deafness. In 2012, "WORLD HEALTH ORGANIZATION" estimated that 5.3% of the world's population had hearing loss, with prevalence in South Asia, Sub-Saharan Africa and Asia Pacific region. In Latin America, the prevalence of 1.6% and specifically in Mexico is estimated that around 10 million people have some type or degree of auditory problem, of which between 200 000 and 400 000 present total deafness. In addition, each year are born between 2000 and 6000 Children with congenital deafness. These numbers show that hearing disorders are an important public health problem around the World [2]. This problem was considered in the National Development plan and in the health Sectoral program 2007–2012, for which the SSA designed the neonatal auditory sieve early intervention program, backed by the standard: NOM-173-SSA1–1998, for comprehensive care for hearing impaired persons [2]. This same recommendation has been Issued by the National Institutes of Health in the USA, in agreement with the American Academy of Pediatrics [3]. The previous

*Alejandra Itzel Contreras Rivas,* 

*and Patricio Guerra Ulloa*

thus avoid delays in neurodevelopment.

OTOAC Sticas Emissions

**1. Introduction**

**Keywords:** hearing defects, hearing loss, neonatal screening,

#### **Chapter 4**

## Neonatal Hearing Screening

*Alejandra Itzel Contreras Rivas, Gaston Eduardo Estudillo Jiménez, Edgar Flores Molina and Patricio Guerra Ulloa*

#### **Abstract**

Around the world 10 million people have some type or degree of auditory problem, of them, between 200,000 and 400,000 have total deafness. Estimating that a large population presents this problem from birth (61%), with an incidence of 1 to 3 of every 1000 newborns. For this reason, early implementation through the neonatal auditory sieve allows timely detection to respond early to the hearing impairment of the newborn, as the ideal age to carry out rehabilitation with the help of an auditory auxiliary and initiate Language therapy is at six months of age. Most of the international guides for the integral attention to persons with auditory disability it indicates that all newborns should be screened Auditory before his hospital discharge. The prevalence of auditory disturbances in our environment is 0.3%, a proportion that places us above national and global statistics, so it is very important to screen all newborns including those who do not have Apparent risk factors in order to establish the appropriate diagnosis, the necessary treatment and thus avoid delays in neurodevelopment.

**Keywords:** hearing defects, hearing loss, neonatal screening, OTOAC Sticas Emissions

#### **1. Introduction**

Hearing loss is the most common neurosensory alteration in the human being, due to the loss or alteration of the anatomical and/or physiological function of the auditory system [1]. It is estimated that worldwide 1 out of every 1000 children is born with bilateral hearing loss. To the deep and 5 out of every 1000 with other forms of deafness. In 2012, "WORLD HEALTH ORGANIZATION" estimated that 5.3% of the world's population had hearing loss, with prevalence in South Asia, Sub-Saharan Africa and Asia Pacific region. In Latin America, the prevalence of 1.6% and specifically in Mexico is estimated that around 10 million people have some type or degree of auditory problem, of which between 200 000 and 400 000 present total deafness. In addition, each year are born between 2000 and 6000 Children with congenital deafness. These numbers show that hearing disorders are an important public health problem around the World [2]. This problem was considered in the National Development plan and in the health Sectoral program 2007–2012, for which the SSA designed the neonatal auditory sieve early intervention program, backed by the standard: NOM-173-SSA1–1998, for comprehensive care for hearing impaired persons [2]. This same recommendation has been Issued by the National Institutes of Health in the USA, in agreement with the American Academy of Pediatrics [3]. The previous

documents establish to make the sieve to all the newborns regardless of their state of health before the discharge hospital, if However most of the countries only reports of children with risk factors, with few compared to healthy children. With the neonatal auditory sieve is intended the timely detection of the hearing impairment of the newborn, its objective is to attend In advance these deficiencies in the neonate, since the ideal age to carry out the rehabilitation with the help of an auditory auxiliary and to initiate the therapy of the language, is at the age of six months, since at this age begins the development of the language. Any reduction in hearing can cause communication disturbances that affect the motor, affective and intellectual development of the individual [3]. Neonatal auditory sieve has several advantages over other methods for detecting no time. Auditory sieve, is 60% less expensive study compared to the neonatal metabolic sieve, faster (lasts about two minutes), immediate response, is not painful and can be repeated as many times as necessary to confirm the outcome [4]. In auditory screening studies a prevalence of permanent congenital hearing loss of 112 by 100,000 infants has been found, with a higher proportion in those who have risk factors (62 by 100,000) than in those who do not have them (54 per 100,000) [5]. There are many different equipment in the market, the most common used in our country is the Portable Interacoustics® OtoRead™ For Sieve Addictive. Provided of a Probe Of 30 Cm o 100 cm, soft latex olives of different calibers. Otoacoustic emissions of distortion products were performed at frequencies 2–5 KHz in four bands with intense. From 40 to 70 db [6]. This is a test that consists in collecting the response of the external hair cells by a receiver placed in the ear canal (CAE), after the sound stimulation by a click, emitted by a microphone in CAE, this technique simple and fast, reproducible, objective, innocuous and reliable: sensitivity: 80–100% and specificity: 90%. It was carried out as recommended by the Commission for the early detection of hearing loss in Spain (COPEDEH).

Phase 1: At birth or before discharge hospital, criterion of the step is the obtaining of the Wave V with PPATC to 40 db or the emission of emissions otoacoustic auditory bilateral.

Phase 2: Newborns who do not exceed this phase are re-explored between the first week and the month of age.

Phase 3: Newborns who do not exceed the second phase are assessed by the audiology service for definitive diagnosis and treatment.

Peripheral hearing is the starting point for structuring expressive language. It is the basis for the comprehension, decoding and central auditory perception to be achieved after reception. These two great phenomena, peripheral sensation and cortical perception, allow the development of the oral language, characteristic and specific quality of the human [7, 8]. The sensations with which the afferent processes begin in the organ of Corti and the babbling with which the first manifesto begins efferent linguistics, are functions that are closely linked to the evolution of Abstract thinking [9]. When hearing does not exist, decreases or is lost, one, several or all psychoacoustic levels are rendered inoperative [10]. We need to be aware that there is a possibility to know if the hearing conditions of newborns are deficit from the first hours after childbirth, which is why it is imperative to act in the stages in which the unstructured as cortical are maturing and can be modeled, as the base as the basis for defining the future of more than 4000 to 6000 babies born deaf or deep hearing problems every year in most of the third world countries [11].

The audiology has its fields of action delimited with great precision, and although many of them correlate with other disciplines, it is the secondary prevention where we can focus the position of our document on the transcendence of sieve Neonatal auditory sieve [12]. The issue that concerns us, the deep hearing loss or total deafness, in many cases with primary prevention measures, it is possible to avoid the damage to the structures of the auditory system and the concomitant

**47**

**2. Benefits**

*Neonatal Hearing Screening*

*DOI: http://dx.doi.org/10.5772/intechopen.95942*

Sensoperceptiva dysfunction [13]. In a percentage these measures cannot be applied, so it is essential to act in the field of secondary prevention to identify a possible problem from the time after birth, so that, continuing with the Diagnosis of certainty and early intervention, the auditory canal is enabled and the cerebral plasticity that will produce the most precious fruit of the audition, which is the language [14], is harnessed. The literature indicates that 0.1% of children are born with some type of congenital deafness [15], according to the results, the prevalence of problems Auditory in healthy newborns of our hospital was 0.3%, i.e. 3 times

The importance of conducting auditory screening at birth is in the timely detection, establishing early rehabilitation, lowering the cost of care for the institution and the health system in general [18, 19] in a systematic review on the prevalence of alterations in neurodevelopment in Mexico, it was identified that reports on the frequency of hearing loss, passed with methodological differences that do not allow the generalization of their results. In addition, The reports in our country are very scarce with high variability of auditory disturbances through auditory screening. However, it should be noted the findings of two studies conducted, one in low-risk population and one with high risk for Auditory problems. In the first group was observed prevalence of 0.65 for every 1000 live births, the second study estimated 2.6% of 6000 children who merited care in a neonatal intensive care unit [20, 21]. In the United States and European countries has prevalence at 5 years of age of 0.5% with estimated people of 800,000, compared to 2.6 million patients in Latin America, the big difference could be given by the prevention and identification of these alterations in Early stages of life. Unattended cases of hearing loss represent an annual global cost of 750 billion. Interventions aimed at preventing, detecting and treating hearing loss are not expensive and may result Very beneficial to the stakeholders. The greatest importance of timely detection is based in the times and degrees in the what the plasticity cerebral and the potential for linguistic development decreases in relation to the age of intervention [22]. The more time it takes for the proper intervention to begin, the more difficult it is for a good development of the oral language to be achieved, which is the basis for the integral development of the individual, which of course includes the mechanisms of written linguistic communication, with the acquisition of reading and writing as starting points of cognitive and cultural development. The critical period for that the intervention is successful is to the 18 months old. Then the potential and plasticity of the brain for the development of the language, until reaching the point where the late interven-

higher than the reported in the literature (3% reported) [16, 17].

tion becomes almost useless [23, 24], quickly decreases.

The benefits of early detection of various medical conditions have long been found; Such is the case of auditory alterations in newborns, an entity that by its very nature is not evident until it is presented retro in neurodevelopment, mainly speech. Unfortunately the ideal age to perform rehabilitation with the help of an auditory assistant and language therapy is at six months of age. Contreras and col. [24] determined that the prevalence of congenital deafness in children without apparent (healthy) risk factors, was three times greater than that reported in the world literature, coupled with this, it is likely that in preterm infants or with various morbidities the prevalence will increase [23]. Therefore, It is essential to educate health providers at all levels of care for the newborn, and the high relevance of hearing screening with an early detection of hearing loss, as well as send it in a timely manner and To receive multidisciplinary management involving specialist in language, audiology,

#### *Neonatal Hearing Screening DOI: http://dx.doi.org/10.5772/intechopen.95942*

Sensoperceptiva dysfunction [13]. In a percentage these measures cannot be applied, so it is essential to act in the field of secondary prevention to identify a possible problem from the time after birth, so that, continuing with the Diagnosis of certainty and early intervention, the auditory canal is enabled and the cerebral plasticity that will produce the most precious fruit of the audition, which is the language [14], is harnessed. The literature indicates that 0.1% of children are born with some type of congenital deafness [15], according to the results, the prevalence of problems Auditory in healthy newborns of our hospital was 0.3%, i.e. 3 times higher than the reported in the literature (3% reported) [16, 17].

The importance of conducting auditory screening at birth is in the timely detection, establishing early rehabilitation, lowering the cost of care for the institution and the health system in general [18, 19] in a systematic review on the prevalence of alterations in neurodevelopment in Mexico, it was identified that reports on the frequency of hearing loss, passed with methodological differences that do not allow the generalization of their results. In addition, The reports in our country are very scarce with high variability of auditory disturbances through auditory screening. However, it should be noted the findings of two studies conducted, one in low-risk population and one with high risk for Auditory problems. In the first group was observed prevalence of 0.65 for every 1000 live births, the second study estimated 2.6% of 6000 children who merited care in a neonatal intensive care unit [20, 21].

In the United States and European countries has prevalence at 5 years of age of 0.5% with estimated people of 800,000, compared to 2.6 million patients in Latin America, the big difference could be given by the prevention and identification of these alterations in Early stages of life. Unattended cases of hearing loss represent an annual global cost of 750 billion. Interventions aimed at preventing, detecting and treating hearing loss are not expensive and may result Very beneficial to the stakeholders. The greatest importance of timely detection is based in the times and degrees in the what the plasticity cerebral and the potential for linguistic development decreases in relation to the age of intervention [22]. The more time it takes for the proper intervention to begin, the more difficult it is for a good development of the oral language to be achieved, which is the basis for the integral development of the individual, which of course includes the mechanisms of written linguistic communication, with the acquisition of reading and writing as starting points of cognitive and cultural development. The critical period for that the intervention is successful is to the 18 months old. Then the potential and plasticity of the brain for the development of the language, until reaching the point where the late intervention becomes almost useless [23, 24], quickly decreases.

#### **2. Benefits**

The benefits of early detection of various medical conditions have long been found; Such is the case of auditory alterations in newborns, an entity that by its very nature is not evident until it is presented retro in neurodevelopment, mainly speech. Unfortunately the ideal age to perform rehabilitation with the help of an auditory assistant and language therapy is at six months of age. Contreras and col. [24] determined that the prevalence of congenital deafness in children without apparent (healthy) risk factors, was three times greater than that reported in the world literature, coupled with this, it is likely that in preterm infants or with various morbidities the prevalence will increase [23]. Therefore, It is essential to educate health providers at all levels of care for the newborn, and the high relevance of hearing screening with an early detection of hearing loss, as well as send it in a timely manner and To receive multidisciplinary management involving specialist in language, audiology,

rehabilitation, otolaryngology, neonatology and psychology in order to promote the increase in the quality of life of these patients, increase the Possi to integrate in a successful and productive way in the society, reduce the costs of care and the socioeconomic cost that causes the country to maintain a problem like the Deafness.

#### **Author details**

Alejandra Itzel Contreras Rivas1 \*, Gaston Eduardo Estudillo Jiménez<sup>2</sup> , Edgar Flores Molina3 and Patricio Guerra Ulloa4

1 The Intensive Neonatal Therapy, Maternal Childhood Hospital Miguel Hidalgo Y Costilla, Mexico

2 Department of Maternal Fetal Medicine, ISSSTE General Hospital Dr. Dario Fernandez Fierro, Mexico

3 Prenatal Care Institute, Chiapas, Mexico

4 ISSSTE General Hospital Dr. Dario Fernandez Fierro, Mexico

\*Address all correspondence to: alejandracontrerasr15@outlook.es

© 2021 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.

**49**

*Neonatal Hearing Screening*

**References**

1057-1063.

130-135.

898-921.

(2007): 421-426.

925-930.

*DOI: http://dx.doi.org/10.5772/intechopen.95942*

[1] Well Ma., et al. "Detection of hearing

Archives of Medical Research 43.6

[11] Delgago Dinar. Martinez But. Merina MM, Pallas And. PeriCase Year. Sanchez RD. et al. "Early detection of infantile hearing loss". Review Primary Care Pediatrics 13 (2011):

[12] Screening for hearing loss in the newborn. Quick Reference Guide.

[13] "Detection of hearing loss in the first level of care". Clinical Practice

[14] Berlanga BO and Sotelo OE. "Neonatal auditory sieve (phase I)". are EMI useful Otacústicas in a healthy stage?" Revid Med inclothe Salud 6.2

[15] Bilateral hearing loss and cochlear

implant. Reference Guide Fast.

[16] González GO and Pérez GV. "Auditory Sieve Clinic at the National Institute of Pediatrics". Pediatric Act of

[17] Socorro Peña Alejandro and Alejandra Itzel Contreras Rivas. "Prevalence of Hearing Loss in Healthy Newborns in a Third-Level Hospital Care by Neonatal Hearing Screening".

Mexico 33.1 (2012): 20-25.

EC Paediatrics 8.9 (2019):

[18] Sandoval-García MA and Iglesias LA. "Frequency of neonatal hearing loss in a private hospital".

908-913.

Guide Update (2012).

(2013): 41-46.

[10] German TR. "Screening techniques in hearing, early detection of deafness program with Transient evoked Oto". In: White Paper on hearing loss early detection of hearing loss in newborn infants. Jaime Ma, Tabernacle ma, editors. Madrid Spain: Rumagraph. His

(2012): 457-463.

of CV 45-89.

279-297.

loss in the neonate". Therapeutic diagnostic Protocols of the ASP: Neonatology 3 (2008): 29-35.

[2] Nicolás AL., et al. "Program of universal screening and Early Intervention (PTUIP) in congenital bilateral neural sensory hearing loss". Medical magazine of Chile 141 (2013):

[3] Wolff RI., et al. "Hearing screening in newborns: systematic review of accuracy, effectiveness, and effects of interventions after screening". Archives of Disease in Childhood 95.2 (2010):

[4] Joint Committe on Infant Hearing. "Year 2007 position statement: principles and guidelines for early hearing detection and interventions programs". Paediatrics 120.4 (2007):

[5] NOM-173-SSA1-1998, for the integral care of hearing-impaired persons.

[6] Hernandez Herrera RI., et al. "Screening and confirmation diagnose hearing loss". High-risk infants vs. open population. Medical Journal of the Mexican Institute of Social Security 45.5

[7] Bielecky take., et al. "Risk factors associated with hearing loss in infants: an analysis of 5282 referred neonates". International Journal of Pediatric Otorhinolaryngology 75.7 (2011):

[8] National Institute of Statistics, Geographic and Informatics (INEGI). People with disabilities in MexICO: a

[9] Martinez CR., et al. "Hearing loss, auditory neuropathy, and neurological co-morbility in childrens with weight".

census vision (2004).

### **References**

[1] Well Ma., et al. "Detection of hearing loss in the neonate". Therapeutic diagnostic Protocols of the ASP: Neonatology 3 (2008): 29-35.

[2] Nicolás AL., et al. "Program of universal screening and Early Intervention (PTUIP) in congenital bilateral neural sensory hearing loss". Medical magazine of Chile 141 (2013): 1057-1063.

[3] Wolff RI., et al. "Hearing screening in newborns: systematic review of accuracy, effectiveness, and effects of interventions after screening". Archives of Disease in Childhood 95.2 (2010): 130-135.

[4] Joint Committe on Infant Hearing. "Year 2007 position statement: principles and guidelines for early hearing detection and interventions programs". Paediatrics 120.4 (2007): 898-921.

[5] NOM-173-SSA1-1998, for the integral care of hearing-impaired persons.

[6] Hernandez Herrera RI., et al. "Screening and confirmation diagnose hearing loss". High-risk infants vs. open population. Medical Journal of the Mexican Institute of Social Security 45.5 (2007): 421-426.

[7] Bielecky take., et al. "Risk factors associated with hearing loss in infants: an analysis of 5282 referred neonates". International Journal of Pediatric Otorhinolaryngology 75.7 (2011): 925-930.

[8] National Institute of Statistics, Geographic and Informatics (INEGI). People with disabilities in MexICO: a census vision (2004).

[9] Martinez CR., et al. "Hearing loss, auditory neuropathy, and neurological co-morbility in childrens with weight". Archives of Medical Research 43.6 (2012): 457-463.

[10] German TR. "Screening techniques in hearing, early detection of deafness program with Transient evoked Oto". In: White Paper on hearing loss early detection of hearing loss in newborn infants. Jaime Ma, Tabernacle ma, editors. Madrid Spain: Rumagraph. His of CV 45-89.

[11] Delgago Dinar. Martinez But. Merina MM, Pallas And. PeriCase Year. Sanchez RD. et al. "Early detection of infantile hearing loss". Review Primary Care Pediatrics 13 (2011): 279-297.

[12] Screening for hearing loss in the newborn. Quick Reference Guide.

[13] "Detection of hearing loss in the first level of care". Clinical Practice Guide Update (2012).

[14] Berlanga BO and Sotelo OE. "Neonatal auditory sieve (phase I)". are EMI useful Otacústicas in a healthy stage?" Revid Med inclothe Salud 6.2 (2013): 41-46.

[15] Bilateral hearing loss and cochlear implant. Reference Guide Fast.

[16] González GO and Pérez GV. "Auditory Sieve Clinic at the National Institute of Pediatrics". Pediatric Act of Mexico 33.1 (2012): 20-25.

[17] Socorro Peña Alejandro and Alejandra Itzel Contreras Rivas. "Prevalence of Hearing Loss in Healthy Newborns in a Third-Level Hospital Care by Neonatal Hearing Screening". EC Paediatrics 8.9 (2019): 908-913.

[18] Sandoval-García MA and Iglesias LA. "Frequency of neonatal hearing loss in a private hospital".

Auditory sieves Revista Mexicana de Pediatría 79.4 (2010): 174-178.

[19] Cordero-Silva MI., et al. "Prevalence of 35delG/GJB2 and del (GJB6-D13S1839) mutations in patient with non-syndromic deafness from pupulation ef Espirutu Santo Brazil". Brazilian Journal of Otorhinolaryngology 76.4 (2010): 428-32.

[20] Flores BL and Berruecos VP. "The problems of hearing in school age: diagnosis identification and treatment of the deaf child". 3rd edition México: threshing (2006).

[21] Berruecos VP. "Diagnosis and treatment of hearing and language problems". In: Narro RJ, López BJ, Rivero SO. Diagnosis and treatment in medical practice, Chapter 12. 4th edition Mexico: The modern handbook and UNAM; (2011): 105-107.

[22] Berruecos VP. "Primary, secondary and tertiary prevention of hearing impairments in Latin America". In: Suzuki J., et al. Hearing impairment: and invisible disability. Tokio: Springer-Verlag (2004): 460-465.

[23] Marquez AI., et al. "Importance of the diagnosis of mutations of the connexin gene 26 in the. Integral management of syndromical congenital deafness". Boletin medico del Hospital Infantil de Mexico 70.2 (2013): 87-89.

[24] Contreras Alejandra, Peña Socorro. Prevalence of Hearing Loss in Healthy Newborns in a Third-Level Hospital Care by Neonatal Hearing Screening. EC Paediatrics 8.9 (2019): 908-913.

**51**

**Chapter 5**

**Abstract**

Cisplatin Ototoxicity in Children

Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many longterm effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of

*Penelope Brock, Kaukab Rajput, Lindsey Edwards,* 

*Annelot Meijer, Philippa Simpkin, Alex Hoetink,* 

*Mariana Kruger, Michael Sullivan* 

*and Marry van den Heuvel-Eibrink*

a child growing up with high frequency hearing loss.

loss and will be the main focus of this chapter [1, 2].

tinnitus, vertigo, prevention

**1. Introduction**

**1.1 Cisplatin**

**Keywords:** cisplatin, chemotherapy, cancer, children, ototoxicity, hearing loss,

Cisplatin is a chemotherapy medicine which can cause hearing loss, tinnitus and vertigo. The most common and well documented toxicity affecting the ear is hearing

Cisplatin was first successfully used in the late 1970s as chemotherapy, in addition to surgery, for the treatment of men with testicular cancer and published in a landmark study in 1980 [3]. At that time Dr. Jon Pritchard at the Great Ormond Street Hospital for Children (GOSH) in London was researching new treatments for

#### **Chapter 5**

## Cisplatin Ototoxicity in Children

*Penelope Brock, Kaukab Rajput, Lindsey Edwards, Annelot Meijer, Philippa Simpkin, Alex Hoetink, Mariana Kruger, Michael Sullivan and Marry van den Heuvel-Eibrink*

#### **Abstract**

Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many longterm effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of a child growing up with high frequency hearing loss.

**Keywords:** cisplatin, chemotherapy, cancer, children, ototoxicity, hearing loss, tinnitus, vertigo, prevention

#### **1. Introduction**

Cisplatin is a chemotherapy medicine which can cause hearing loss, tinnitus and vertigo. The most common and well documented toxicity affecting the ear is hearing loss and will be the main focus of this chapter [1, 2].

#### **1.1 Cisplatin**

Cisplatin was first successfully used in the late 1970s as chemotherapy, in addition to surgery, for the treatment of men with testicular cancer and published in a landmark study in 1980 [3]. At that time Dr. Jon Pritchard at the Great Ormond Street Hospital for Children (GOSH) in London was researching new treatments for childhood cancer and had a particular patient with widespread ovarian cancer who would previously have been moved to palliative care. However, seeing the effect of cisplatin on testicular cancer in young men, he thought it might work on ovarian cancer in young women and got urgent permission to treat his patient with this new medication. The child's tumour had a spectacular response and shrank enough for the surgeon, at the time Professor Spitz, to successfully remove the tumour without having to perform a hysterectomy. She was cured and when she had children of her own, Jon became Godfather to her first child. The History of cisplatin and its introduction to medicine was captured by The Wellcome Trust in 2006 [4].

However, the challenge of introducing this powerful new chemotherapy to treat children with cancer was its toxicity, it was extremely emetogenic provoking severe nausea and vomiting, and was toxic to the kidneys (renal toxicity), ears (ototoxicity) and peripheral nervous system (neurotoxicity). Research into the side effects of this medicine on children at GOSH began in 1985 when Dimitrios Kouliouskas started studying the renal toxicity [5, 6].

In 1987, both in Brussels and London, a combination treatment of cisPLAtin and DOxorubicin was showing promise in the treatment of children with large liver tumours (hepatoblastoma). These tumours need expert surgery to remove the whole tumour intact; this combination was able to shrink hepatoblastomas to make surgery safer and in some cases make it possible to remove previously unresectable tumours. It was Jon Pritchard who coined the phrase "PLADO" for this combination treatment when passing a Play-Doh store on the way back to the airport in Brussels. Later that same year at the annual meeting of the International Society of Paediatric Oncology (SIOP) in Jerusalem Jon, along with Dr. Jacques Plaschkes (Paediatric Surgeon, Berne), Dr. Giorgio Perilongo (Padua) and others formed the International Society of Paediatric Oncology Epithelial Liver group SIOPEL to improve the treatment of children with liver cancer.

With increased use of cisplatin an alarming incidence of hearing loss was observed and at GOSH, Consultant Audiologist Sue Bellman noted a striking pattern seen on hearing tests (audiograms). Audiograms are a measure of the intensity of sound in decibels (dB) required for a person to hear a particular frequency measured in Hertz (Hz). The patterns seen in children with cisplatin-related hearing loss were very consistent and led to the development of an ototoxicity grading scale (the Brock Grading Scale) which could be used to evaluate the hearing loss acquired by one child and compare it to that of other children treated with cisplatin [7]. In this way different treatment regimens of cisplatin could be compared for ototoxicity. The grading scale showed that some children were more susceptible to cisplatin ototoxicity compared to others when given the same cumulative dose. This idiosyncratic and varied severity suggests possible biological or genetic susceptibility to hearing loss and has led to years of study of the genetic predisposition of patients towards cisplatin ototoxicity.

Cisplatin remains one of the most effective chemotherapy drugs for childhood cancer and is a key component in the treatment of solid tumours, specifically, malignant germ cell tumours, liver tumours, neuroblastoma, osteosarcoma and retinoblastoma, but also brain tumours, particularly medulloblastoma and ependymoma. However, the occurrence of irreversible hearing loss that occurs in approximately 50% of cisplatin-treated children, is a serious clinical challenge [8–10].

The impact of the hearing loss, tinnitus and potentially vertigo caused by cisplatin has serious consequences for the child, their family and the society in which they live [11]. Very young children with even mild forms of hearing loss have difficulty developing the skills of language leading to communication problems and reduced school performance [1]. Acquired hearing loss in adolescents with previously normal hearing, causes serious social and emotional difficulties [12].

**53**

**Figure 1.** *The ear.*

*Cisplatin Ototoxicity in Children*

**1.2 Hearing and balance**

(the organ of balance), see **Figure 1**.

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

autologous bone marrow transplantation, it is ototoxic.

In children with brain tumours, cisplatin-related ototoxicity is made more debilitating by damage to the hearing from surgery and radiotherapy, and ototoxicity may compound the learning difficulties caused by radiation to the whole brain. Other platinum based medications have been developed, (carboplatin and oxaliplatin), with the aim of reducing toxicity but they do not have the efficacy in many cancers to replace cisplatin except in certain circumstances. Carboplatin, which is now widely used in childhood cancer, is less ototoxic (its main toxicity is to bone marrow), but it cannot be substituted for cisplatin without careful clinical trial evidence that it is as effective. When used in combination with cisplatin, the combined ototoxicity is greater than the sum of the two individual drugs [13]. When carboplatin is used at high dose, such as for bone marrow ablation prior to

As it is unlikely cisplatin will be replaced by other agents to treat childhood cancer any time soon, monitoring its impact on a child's development and education, increasing awareness of its effects and support for families, and finding ways to prevent ototoxicity are the key medical needs for the foreseeable future. The results of recent oto-protection clinical trials testing agents to mitigate cisplatin hearing loss have recently been assessed and a clinical guideline published [14, 15].

Hearing and balance are the two senses that are perceived by means of the inner ear that consists of the cochlea (the organ of hearing) and the vestibular system

Hearing is the perception of sound and the vestibular system detects motion of the head and body. Together with vision and propriosepsis, which is the internal sense of positioning within the body, these senses are elementary for orientation and sense of safety in the world. For the developing child, normal hearing is essential to learn to detect, discriminate and identify sounds, culminating in the ability to use and understand spoken language, enjoy music and identify potential harm. A normal function of the vestibular system is essential for learning to move freely and efficiently. The importance of hearing for the development of speech

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

In children with brain tumours, cisplatin-related ototoxicity is made more debilitating by damage to the hearing from surgery and radiotherapy, and ototoxicity may compound the learning difficulties caused by radiation to the whole brain.

Other platinum based medications have been developed, (carboplatin and oxaliplatin), with the aim of reducing toxicity but they do not have the efficacy in many cancers to replace cisplatin except in certain circumstances. Carboplatin, which is now widely used in childhood cancer, is less ototoxic (its main toxicity is to bone marrow), but it cannot be substituted for cisplatin without careful clinical trial evidence that it is as effective. When used in combination with cisplatin, the combined ototoxicity is greater than the sum of the two individual drugs [13]. When carboplatin is used at high dose, such as for bone marrow ablation prior to autologous bone marrow transplantation, it is ototoxic.

As it is unlikely cisplatin will be replaced by other agents to treat childhood cancer any time soon, monitoring its impact on a child's development and education, increasing awareness of its effects and support for families, and finding ways to prevent ototoxicity are the key medical needs for the foreseeable future. The results of recent oto-protection clinical trials testing agents to mitigate cisplatin hearing loss have recently been assessed and a clinical guideline published [14, 15].

#### **1.2 Hearing and balance**

Hearing and balance are the two senses that are perceived by means of the inner ear that consists of the cochlea (the organ of hearing) and the vestibular system (the organ of balance), see **Figure 1**.

Hearing is the perception of sound and the vestibular system detects motion of the head and body. Together with vision and propriosepsis, which is the internal sense of positioning within the body, these senses are elementary for orientation and sense of safety in the world. For the developing child, normal hearing is essential to learn to detect, discriminate and identify sounds, culminating in the ability to use and understand spoken language, enjoy music and identify potential harm. A normal function of the vestibular system is essential for learning to move freely and efficiently. The importance of hearing for the development of speech

and spoken language is well recognised and in several countries national newborn hearing screening programs have been implemented to detect congenital hearing loss as early as possible, and enable timely intervention. Hearing loss has many impacts on daily auditory functioning, communication, psychosocial wellbeing, and general health, so high quality hearing care for children is best delivered by multidisciplinary teams consisting of medical specialists, audiologists, speech language therapists and (developmental) psychologists. Acquired hearing loss may have multiple causes, but one of the common causes in childhood follows treatment for childhood cancer with cisplatin.

For a sound to be perceived, it has to travel through the external ear, the middle ear, the cochlea and the auditory nervous system to the auditory cortex in the brain. Sound waves are collected by the pinna and channelled by the external auditory canal to the tympanic membrane, causing it to vibrate. The middle ear is an air-filled cavity containing the ossicles (malleus, incus and stapes). The footplate of the malleus rests on the eardrum (tympanic membrane). When the membrane vibrates in response to sound it causes movement of the malleus. This movement is, in turn, transmitted via the incus and the stapes to the fluid filled cochlea.

The normal cochlea is a coiled structure with two and a half turns. It is divided lengthways into three fluid-filled compartments by two membranes (the basilar and Reissner's membrane). These create three fluid filled spaces, the scala tympani is the lower compartment, the cochlear duct (scala media) the middle one and the scala vestibuli the upper compartment, as shown in **Figure 2**. The inner ear hearing apparatus (the organ of Corti) consists of two types of sensory hair cells, the inner hair cells and the outer hair cells, resting on the basilar membrane, also shown in **Figure 2**.

When the middle ear stapes footplate moves, pressure waves in the cochlear fluid produce movement of the basilar membrane and the inner and outer hair cells in the organ of Corti. Excitation on the surface of the inner hair cells creates a neurotransmitter impulse which is transmitted along the cochlear nerve (VIIIth

**55**

effects of cisplatin.

(**Figure 3**).

*Cisplatin Ototoxicity in Children*

lymphoma.

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

with the highest sound frequencies lost first.

**2. Cisplatin and cisplatin-related toxicity**

**2.1 Cisplatin mechanism of action**

cranial nerve) to the brain stem and auditory region of the brain. Damage to both the inner and outer hair cells from cisplatin, causes loss of this signal transmission,

Childhood cancer is divided into haematological cancer and solid tumours. Haematological cancers occur in the bone marrow and lymph glands (leukaemia and lymphoma) and solid tumours occur in organs such as the liver, kidneys and nerves; solid tissues such as bone and muscle; and the brain (brain and spinal tumours). Cisplatin is currently used alone or in combination with other chemotherapy to treat solid tumours and brain tumours, and only rarely for leukaemia or

When given to children intravenously cisplatin causes acute nausea and vomiting, and may cause renal impairment (nephrotoxicity), neurotoxicity and ototoxicity. When given to adult patients, the dose limiting toxicity is neurological (peripheral neuropathy, tinnitus and vertigo) whereas in children its major long-term effect is ototoxicity with permanent irreversible hearing loss. The severity of ototoxicity varies with age being more severe in younger children, the dose of cisplatin administered at each treatment and cumulative dose of cisplatin given during the course of treatment. However, susceptibility to these effects and their severity vary from individual to individual. Some children will develop very little toxicity despite large cumulative doses and others will develop relatively severe toxicity with only one or a few doses. The significant heterogeneity in the occurrence of ototoxicity among similarly treated patients, suggests that genetic susceptibility contributes to the occurrence of cisplatin-related hearing loss in individual children [16–19] (section 2.5.3).

Cisplatin is a simple chemical compound made up of an atom of the platinum metal bound with two atoms of chlorine on one side (cis) and two molecules of ammonia on the other side. When in solution in the blood surrounded by a high concentration of chloride ions cisplatin remains in its neutral form. However, when cisplatin enters a normal cell or a cancer cell which has lower concentrations of chloride ions, cisplatin undergoes spontaneous hydrolysis with water. In this activated state it can enter the nucleus of a cell and become irreversibly bound into the double strands of nuclear DNA forming a cisplatin-DNA adduct

Both normal and cancer cells have complex molecular mechanisms that have evolved to repair the damage to DNA caused by toxins such as cisplatin and other chemotherapy agents. If a cell can activate its molecular repair mechanism and successfully repair the damaged DNA, it will survive and continue to thrive, but if the damage is irreparable, both normal and cancer cells can switch on a molecular process called programmed cell death (apoptosis) and the affected cell will die. Cells can also resist the effect of cisplatin by producing free radicle oxygen molecules within the cell cytoplasm that neutralise the cisplatin molecule. The use of cisplatin in the treatment of children with cancer relies on the fact that solid tumour cancer cells are less able to repair DNA damage than normal cells, and are less resistant to cisplatin, making them more susceptible to apoptosis than the child's normal tissues. However, within the cells of some normal tissues such as within the hearing apparatus, the kidney and peripheral nerves are directly damaged by the

**Figure 2.** *Cross section of the cochlear scalae in the basal turn.*

cranial nerve) to the brain stem and auditory region of the brain. Damage to both the inner and outer hair cells from cisplatin, causes loss of this signal transmission, with the highest sound frequencies lost first.

#### **2. Cisplatin and cisplatin-related toxicity**

Childhood cancer is divided into haematological cancer and solid tumours. Haematological cancers occur in the bone marrow and lymph glands (leukaemia and lymphoma) and solid tumours occur in organs such as the liver, kidneys and nerves; solid tissues such as bone and muscle; and the brain (brain and spinal tumours). Cisplatin is currently used alone or in combination with other chemotherapy to treat solid tumours and brain tumours, and only rarely for leukaemia or lymphoma.

When given to children intravenously cisplatin causes acute nausea and vomiting, and may cause renal impairment (nephrotoxicity), neurotoxicity and ototoxicity. When given to adult patients, the dose limiting toxicity is neurological (peripheral neuropathy, tinnitus and vertigo) whereas in children its major long-term effect is ototoxicity with permanent irreversible hearing loss. The severity of ototoxicity varies with age being more severe in younger children, the dose of cisplatin administered at each treatment and cumulative dose of cisplatin given during the course of treatment. However, susceptibility to these effects and their severity vary from individual to individual. Some children will develop very little toxicity despite large cumulative doses and others will develop relatively severe toxicity with only one or a few doses. The significant heterogeneity in the occurrence of ototoxicity among similarly treated patients, suggests that genetic susceptibility contributes to the occurrence of cisplatin-related hearing loss in individual children [16–19] (section 2.5.3).

#### **2.1 Cisplatin mechanism of action**

Cisplatin is a simple chemical compound made up of an atom of the platinum metal bound with two atoms of chlorine on one side (cis) and two molecules of ammonia on the other side. When in solution in the blood surrounded by a high concentration of chloride ions cisplatin remains in its neutral form. However, when cisplatin enters a normal cell or a cancer cell which has lower concentrations of chloride ions, cisplatin undergoes spontaneous hydrolysis with water. In this activated state it can enter the nucleus of a cell and become irreversibly bound into the double strands of nuclear DNA forming a cisplatin-DNA adduct (**Figure 3**).

Both normal and cancer cells have complex molecular mechanisms that have evolved to repair the damage to DNA caused by toxins such as cisplatin and other chemotherapy agents. If a cell can activate its molecular repair mechanism and successfully repair the damaged DNA, it will survive and continue to thrive, but if the damage is irreparable, both normal and cancer cells can switch on a molecular process called programmed cell death (apoptosis) and the affected cell will die. Cells can also resist the effect of cisplatin by producing free radicle oxygen molecules within the cell cytoplasm that neutralise the cisplatin molecule. The use of cisplatin in the treatment of children with cancer relies on the fact that solid tumour cancer cells are less able to repair DNA damage than normal cells, and are less resistant to cisplatin, making them more susceptible to apoptosis than the child's normal tissues. However, within the cells of some normal tissues such as within the hearing apparatus, the kidney and peripheral nerves are directly damaged by the effects of cisplatin.

**Figure 3.** *Cisplatin structure and mechanism of action [20].*

#### **2.2 Cisplatin administration**

Cisplatin is administered intravenously. It is infused via a central venous catheter over various times but usually between 1 and 6 hours, and given with a large amount of hydration fluid with a high chloride concentration to reduce its toxicity. The hydration is usually administered over 24 hours so the child must stay in hospital during its administration. If the child is not hospitalised throughout this time, adequate hydration needs to be managed by other means.

In the early years, cisplatin was administered for an hour following a period of hydration of about 6 hours, with another 24 hours hydration afterwards.

Times of administration of cisplatin began to lengthen in the late 1980's when it was found that lengthening the infusion time reduced the severity of the nausea and vomiting the child experienced. Cisplatin infusion times in Europe reached up to 96 hours continuous infusion. However, with the introduction of new classes of antiemetic drugs in the 1990's, specifically the HT3 inhibitors (ondansetron and others) the cisplatin infusion times were able to be reduced [20].

In some settings and for some cancers, the dose of cisplatin was split over 5 days reducing the need for 24-hour hydration and hospitalisation. So, in place of a standard dose, and very emetogenic dose of 100 mg/m<sup>2</sup> on one day, 20 mg/m<sup>2</sup> would be given on day 1 through 5.

#### **2.3 Cisplatin and emesis**

Cisplatin is highly emetogenic. The nausea and vomiting which ensues appears to be universal. Fortunately, the introduction of the HT3 inhibitors in the 1990s and additional classes of antiemetics more recently, the severity of emesis can be greatly modified in most children [20]. However, effective antiemesis requires a cocktail of antiemetics to be given at least 30 minutes prior to administering cisplatin and that the best antiemetic control is achieved from the very first cisplatin dose. Inadequate antiemetic treatment at the start of cisplatin therapy can lead to the development of anticipatory vomiting which is a particular problem in adolescents. This is when a patient starts to vomit when the idea of receiving chemotherapy is triggered for example on sight of the hospital or if they meet a

**57**

window membrane.

*Cisplatin Ototoxicity in Children*

is very difficult to control.

improvement [5, 6].

tant for speech [7].

*2.5.1 How cisplatin enters the ear*

**2.5 Cisplatin ototoxicity**

**2.4 Cisplatin nephrotoxicity**

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

ward staff member in a shop. Once anticipatory vomiting has become established it

Cisplatin is almost entirely excreted through the kidney. When in its ionised form, cisplatin is very toxic to kidneys, so to ensure cisplatin is excreted in nonionised form it needs a high concentration of chloride ions in the posthydration fluid. Nephrotoxicity in young children is partially reversible although this may be due to further maturation of the kidney in very young children rather than actual

The hearing loss caused by cisplatin is permanent and bilateral and it may worsen with time. It is worse in very young children, the ear at this age appears to be more susceptible to damage compared to that in older children and adults. Cisplatin causes high frequency hearing loss which may happen following the first cycle of treatment and once acquired it tends to worsen with increasing cumulative doses of cisplatin and eventually may spread towards the lower frequencies impor-

Cisplatin enters the inner ear or cochlea through a number of molecular transport pathways as shown in **Figure 4** [21]. The cochlea (and vestibulum) are surrounded by several distinct barriers separating the inner ear vasculature and the inner ear fluid compartments that are filled with perilymph, endolymph or intrastrial fluid. Their anatomical sites are not yet clearly identified, but Neiberg et al. [22] summarise them as follows: "tightly coupled vascular endothelial cells form the blood-perilymph or blood-labyrinth barrier (BLB)". The same authors consider the separation between blood, endolymph and intrastrial fluid as being more complex: "tightly coupled strial endothelial cells form the barrier between blood and intrastrial fluid". This latter is separated from endolymph by epithelial marginal cells in conjunction with endothelial basal cells from the intrastrial compartment. These are also referred to as the blood-strial barrier or intrastrial fluid-blood barrier. The

The BLB plays an important role in cochlear homeostasis to maintain its functional integrity. As a highly specialised capillary network it selectively allows the passage of nutrients and ions in and out of the cochlea, and functions as a shield to protect the inner ear from toxic agents. However, cisplatin seems to affect the stria vascularis and might cause breakdown of the BLB [23]. The permeability of the BLB is also influenced by inflammation, diuretics, noise and a number of other factors [22]. Several organs including the liver, spleen and kidneys are able to rapidly clear cisplatin and its derivatives. Due to its unique structure, however, this ability is considered to be low for the cochlea [24]. Thus, the BLB may serve as a port of entry for cisplatin, from which it is hard to escape. Cisplatin may be retained in the cochlea for several months to years after treatment [24]. Another drawback of the BLB that is mentioned in [22] is the difficulty it poses to deliver otoprotective agents to the cochlea, as systemic delivery is highly inefficient, while local delivery is inherently invasive with limited permeability of the round

more general use of the term BLB covers all of these barriers.

ward staff member in a shop. Once anticipatory vomiting has become established it is very difficult to control.

#### **2.4 Cisplatin nephrotoxicity**

Cisplatin is almost entirely excreted through the kidney. When in its ionised form, cisplatin is very toxic to kidneys, so to ensure cisplatin is excreted in nonionised form it needs a high concentration of chloride ions in the posthydration fluid. Nephrotoxicity in young children is partially reversible although this may be due to further maturation of the kidney in very young children rather than actual improvement [5, 6].

#### **2.5 Cisplatin ototoxicity**

The hearing loss caused by cisplatin is permanent and bilateral and it may worsen with time. It is worse in very young children, the ear at this age appears to be more susceptible to damage compared to that in older children and adults. Cisplatin causes high frequency hearing loss which may happen following the first cycle of treatment and once acquired it tends to worsen with increasing cumulative doses of cisplatin and eventually may spread towards the lower frequencies important for speech [7].

#### *2.5.1 How cisplatin enters the ear*

Cisplatin enters the inner ear or cochlea through a number of molecular transport pathways as shown in **Figure 4** [21]. The cochlea (and vestibulum) are surrounded by several distinct barriers separating the inner ear vasculature and the inner ear fluid compartments that are filled with perilymph, endolymph or intrastrial fluid. Their anatomical sites are not yet clearly identified, but Neiberg et al. [22] summarise them as follows: "tightly coupled vascular endothelial cells form the blood-perilymph or blood-labyrinth barrier (BLB)". The same authors consider the separation between blood, endolymph and intrastrial fluid as being more complex: "tightly coupled strial endothelial cells form the barrier between blood and intrastrial fluid". This latter is separated from endolymph by epithelial marginal cells in conjunction with endothelial basal cells from the intrastrial compartment. These are also referred to as the blood-strial barrier or intrastrial fluid-blood barrier. The more general use of the term BLB covers all of these barriers.

The BLB plays an important role in cochlear homeostasis to maintain its functional integrity. As a highly specialised capillary network it selectively allows the passage of nutrients and ions in and out of the cochlea, and functions as a shield to protect the inner ear from toxic agents. However, cisplatin seems to affect the stria vascularis and might cause breakdown of the BLB [23]. The permeability of the BLB is also influenced by inflammation, diuretics, noise and a number of other factors [22]. Several organs including the liver, spleen and kidneys are able to rapidly clear cisplatin and its derivatives. Due to its unique structure, however, this ability is considered to be low for the cochlea [24]. Thus, the BLB may serve as a port of entry for cisplatin, from which it is hard to escape. Cisplatin may be retained in the cochlea for several months to years after treatment [24]. Another drawback of the BLB that is mentioned in [22] is the difficulty it poses to deliver otoprotective agents to the cochlea, as systemic delivery is highly inefficient, while local delivery is inherently invasive with limited permeability of the round window membrane.

#### **Figure 4.**

*Model of the cochlea and cisplatin (Pt) trafficking routes. Potential pathways for systemic Pt to cross the blood-labyrinth barrier and enter hair cells include (1) a transstrial trafficking route from strial capillaries to marginal cells, followed by clearance into endolymph; (2,3) traversing the blood lymph barrier into perilymph and subsequently into endolymph via transcytosis across the epithelial perilymph/endolymph barrier. (4) once in endolymph, Pt enters haircells across their apical membranes. (5) Pt in the scala tympani could also pass through the basilar membrane into extra cellular fluids within the organ of Corti and enter haircells across their basolateral membranes. S stria vascularis; F spirocytes in spiral ligament [22].*

#### *2.5.2 Destruction of the hair cells of the cochlea*

Cisplatin causes irreversible damage to the hair cells of the cochlear apparatus located in the inner ear. Once within the perilymph cisplatin may remain permanently trapped in the inner ear and may continue to cause delayed hearing loss [24]. The molecular mechanism of cisplatin related ototoxicity and destruction of the hair cells is currently unknown. It is thought to involve the production and activation of Reactive Oxygen Species, (ROS), within the cell cytoplasm which the cell attempts to neutralise by a specific molecular mechanism. However, the capacity of the hair cells to neutralise ROS may become exhausted with time or exceeded by the cisplatin dose, leading to hair cell death. Hair cells in the cochlea are fixed in number and do not regrow, so once destroyed hearing begins to be lost. This would explain why higher doses of cisplatin given per day cause more toxicity. **Figure 5** shows how the hydrated complex is neutralised by the cell [25].

#### *2.5.3 Genetic susceptibility to hearing impairment*

Over the years, several studies have focused on genetic susceptibility to cisplatin-induced hearing loss using candidate single nucleotide polymorphism (SNP) approaches and more recently genome wide association studies (GWAS). Results to date are conflicting, as studies were often underpowered and did not included multiple testing or replication efforts. Differences in patient populations (e.g., ancestry), sample size, methods of audiometric testing and end point definitions with regards to audiological testing or classification attributable factors that may explain these discrepancies in results and have shown, that certain cohort and

**59**

**Figure 5.**

nervous system.

*Cisplatin Ototoxicity in Children*

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

treatment factors (e.g. cranial irradiation, type of platinum agent, total cumulative doses and use of co-medication) may be even more important than genetic susceptibility. In addition, comparison of genetic studies to date have been hampered by

*cis-diammine(aqua)chloroplatinum(II) (a monohydrate cisplatin complex) upon entering the cell cytoplasm.* 

*detoxified by superoxide dismutase (SOD) to hydrogen peroxide (H2O2) and oxygen. Hydrogen peroxide is further detoxified by catalase to water (H2O) and oxygen. Cisplatin reactive intermediates readily bind to and oxidise the antioxidant reduced glutathione (GSH) to oxidised glutathione (GSSH). Glutathione peroxidase (GSH.Px) consumes GSH to produce glutathione disulfide (GSSG) in the process of converting H2O2 to H2O. Glutathione reductase (GR) reduces GSSR to GSH by using the reduced form of nicotinamide adenine* 

*−−) which is* 

*Cisplatin's interaction with the cochlear antioxidant defence system. Cisplatin is converted to a* 

*These reactive platinum species can react with molecular oxygen (O2) to generate superoxide (O2*

Currently, efforts are being made to identify and meta-analyse relevant genetic variants, to enable the selection of children with a high risk of platinum related hearing loss to facilitate clinical decision making and where possible to intervene to prevent ototoxic damage. Alongside intensifying hearing screening any other intervention would require careful clinical risk assessment aided by thoughtful discussions with parents, carers and older children themselves. This could then lead

Functional hearing is represented by 'air conduction' thresholds measured using headphones, and 'bone conduction' thresholds measured using a vibrator placed on the mastoid bone. The air conduction thresholds indicate the status of the external ear, middle ear, cochlea and central auditory nervous system. The bone conduction thresholds indicate the status of only the cochlea and central auditory

heterogeneity in phenotype definitions **Table 1** [26–28].

*dinucleotide phosphate (NADP+) NADPH, as cofactor [24].*

*2.5.4 Hearing assessment in children*

to agreeing on an alternative cancer treatment plan for the child [29].

#### **Figure 5.**

*Cisplatin's interaction with the cochlear antioxidant defence system. Cisplatin is converted to a cis-diammine(aqua)chloroplatinum(II) (a monohydrate cisplatin complex) upon entering the cell cytoplasm. These reactive platinum species can react with molecular oxygen (O2) to generate superoxide (O2 −−) which is detoxified by superoxide dismutase (SOD) to hydrogen peroxide (H2O2) and oxygen. Hydrogen peroxide is further detoxified by catalase to water (H2O) and oxygen. Cisplatin reactive intermediates readily bind to and oxidise the antioxidant reduced glutathione (GSH) to oxidised glutathione (GSSH). Glutathione peroxidase (GSH.Px) consumes GSH to produce glutathione disulfide (GSSG) in the process of converting H2O2 to H2O. Glutathione reductase (GR) reduces GSSR to GSH by using the reduced form of nicotinamide adenine dinucleotide phosphate (NADP+) NADPH, as cofactor [24].*

treatment factors (e.g. cranial irradiation, type of platinum agent, total cumulative doses and use of co-medication) may be even more important than genetic susceptibility. In addition, comparison of genetic studies to date have been hampered by heterogeneity in phenotype definitions **Table 1** [26–28].

Currently, efforts are being made to identify and meta-analyse relevant genetic variants, to enable the selection of children with a high risk of platinum related hearing loss to facilitate clinical decision making and where possible to intervene to prevent ototoxic damage. Alongside intensifying hearing screening any other intervention would require careful clinical risk assessment aided by thoughtful discussions with parents, carers and older children themselves. This could then lead to agreeing on an alternative cancer treatment plan for the child [29].

#### *2.5.4 Hearing assessment in children*

Functional hearing is represented by 'air conduction' thresholds measured using headphones, and 'bone conduction' thresholds measured using a vibrator placed on the mastoid bone. The air conduction thresholds indicate the status of the external ear, middle ear, cochlea and central auditory nervous system. The bone conduction thresholds indicate the status of only the cochlea and central auditory nervous system.


*\*SNPS that were tested once, but not found to be associated with ototoxicity were not included. CR = conflicting result CDA = candidate gene approach. #: studies that adjusted for multiple testing.*

*(1)Thiesen, Pharmacogenetics and genomics, 2017; (2)Vos,Ppharmacogenetics and genomics, 2016; (3)Hagleitner, PloSone, 2014; (4)Yang, Clinical Pharmacology and Therapeutics, 2013; (5)Rednam, 2013; (6)Pusegoda, Clinical Pharmacology and Therapeutics 2013; (7)Choeypasert,2013;, (8)Riedeman, 2008; (9)Knoll, Laryngoscope, 2006; (10)Peters, AntiCancer drugs, 2000; (11)Brown,Cancer Med, 2015; (12)Ross, Nat Gen, 2009; (13) Xu, Nat Gen, 2015; (14) Wheeler, Clin Cancer Research, 2017; (15)Langer, EJC, 2020).*

#### **Table 1.**

*Relevant SNP studies on cisplatin related hearing loss in childhood cancer by candidate gene studies\* .*

#### *2.5.4.1 Testing of the status of the external and middle ear*

A check-up of external - and middle ear status is required to exclude any conditions causing obstruction for the sound to reach the cochlea. When sound is

**61**

**Figure 6.**

*Utrecht University; 2021).*

*Cisplatin Ototoxicity in Children*

ment and motivation.

the right.

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

*2.5.4.2 Behavioural testing of inner ear status*

provide useful information about the status of the middle ear.

obstructed from reaching the cochlea, this is called a conductive hearing loss. Causes for conductive hearing loss include accumulation of cerumen, infections or tympanic membrane perforation [30]. Otoscopy allows for visual inspection of the auditory canal, the tympanic membrane and part of the middle ear. Tympanometry may be used to indicate the presence of middle ear pathology, by measuring the mechanoacoustic properties of the middle ear system [31]. A probe is placed in the ear canal for a few seconds, which delivers a tone and changes the air pressure. The way in which the pressure changes affect the sound level developed in the ear canal can

Several behavioural tests are available to estimate hearing thresholds in children. The reliability of these tests depends on the child's age, neurological status, develop-

The usual way to assess hearing function in older children and adults is to measure the air and bone conduction thresholds, i.e. the quietest sounds which can be detected, as most hearing problems are associated with raised (poorer) thresholds. Audiometry is the process of measuring hearing thresholds at a range of frequencies (pitches). Thresholds may be measured in various ways and are usually displayed on an audiogram, which shows the thresholds at each audiometric frequency. Different types of hearing loss and their classifications can be found in a previous IntechOpen book [32]. **Figure 6** shows a typical Pure Tone Audiogram of normal hearing on the left and moderate cisplatin induced high frequency sensorineural hearing loss on

The horizontal axis shows the test frequencies. Octave intervals are tested from 125 or 250 to 8000 Hz (8 kHz). The vertical axis is the level of sound in decibels termed dB HL (Hearing Level) where the quietest levels are at the top. Thus, the "normal range" is anything down to 20 dB HL (vertical axis) and thresholds higher than 20 dB HL (lower on the audiogram) represent a clinically significant hearing loss. Where there is no conductive hearing loss the air - and bone conduction

*An audiogram showing normal hearing on the left, and an audiogram depicting a typically symmetrical high frequency hearing loss on the right. The red line represents the results for the right ear, and the blue line the results for the left ear. The x-axis portrays the frequency of sound in hertz, and the y-axis the hearing level in decibel with acoustic reference zero for calibration given in ISO-381-1 for frequencies up to 8 kHz and in ISO-381-5 for the extended high frequencies (Meijer A.J.M. Childhood cancer related hearing loss and tinnitus.* 

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

obstructed from reaching the cochlea, this is called a conductive hearing loss. Causes for conductive hearing loss include accumulation of cerumen, infections or tympanic membrane perforation [30]. Otoscopy allows for visual inspection of the auditory canal, the tympanic membrane and part of the middle ear. Tympanometry may be used to indicate the presence of middle ear pathology, by measuring the mechanoacoustic properties of the middle ear system [31]. A probe is placed in the ear canal for a few seconds, which delivers a tone and changes the air pressure. The way in which the pressure changes affect the sound level developed in the ear canal can provide useful information about the status of the middle ear.

#### *2.5.4.2 Behavioural testing of inner ear status*

Several behavioural tests are available to estimate hearing thresholds in children. The reliability of these tests depends on the child's age, neurological status, development and motivation.

The usual way to assess hearing function in older children and adults is to measure the air and bone conduction thresholds, i.e. the quietest sounds which can be detected, as most hearing problems are associated with raised (poorer) thresholds. Audiometry is the process of measuring hearing thresholds at a range of frequencies (pitches). Thresholds may be measured in various ways and are usually displayed on an audiogram, which shows the thresholds at each audiometric frequency. Different types of hearing loss and their classifications can be found in a previous IntechOpen book [32]. **Figure 6** shows a typical Pure Tone Audiogram of normal hearing on the left and moderate cisplatin induced high frequency sensorineural hearing loss on the right.

The horizontal axis shows the test frequencies. Octave intervals are tested from 125 or 250 to 8000 Hz (8 kHz). The vertical axis is the level of sound in decibels termed dB HL (Hearing Level) where the quietest levels are at the top. Thus, the "normal range" is anything down to 20 dB HL (vertical axis) and thresholds higher than 20 dB HL (lower on the audiogram) represent a clinically significant hearing loss. Where there is no conductive hearing loss the air - and bone conduction

#### **Figure 6.**

*An audiogram showing normal hearing on the left, and an audiogram depicting a typically symmetrical high frequency hearing loss on the right. The red line represents the results for the right ear, and the blue line the results for the left ear. The x-axis portrays the frequency of sound in hertz, and the y-axis the hearing level in decibel with acoustic reference zero for calibration given in ISO-381-1 for frequencies up to 8 kHz and in ISO-381-5 for the extended high frequencies (Meijer A.J.M. Childhood cancer related hearing loss and tinnitus. Utrecht University; 2021).*

**Figure 7.** *The speech banana.*

thresholds are more or less the same, but when there is a hearing loss the air conduction thresholds are depressed further.

**Figure 7** shows the levels and conductive frequencies of a variety of environmental sounds and components of speech (the so-called "speech banana") in an audiogram format. Overlaying any audiogram onto this can indicate which sounds are audible and those which would be inaudible, which can illustrate the functional implications of various configurations of hearing loss.

For the results of audiometry to be reliable, the child has to understand the instructions and has to be motivated to comply. For children younger than 5 years of age, audiometry is generally too challenging. Therefore, several other behavioural tests are available to estimate hearing thresholds in children. The reliability of these tests depends on the child's age, neurological status, development and motivation.

Visual reinforcement audiometry is applied to estimate hearing thresholds in young children (6 months to 3 years of age). A visual reinforcer, such as an animated toy or picture is used to generate and maintain a head turn response to the sound stimulus presented through a speaker or ear phones.

To measure hearing thresholds in children aged 3 to 5 years, conditioned play audiometry may be applied. The child is conditioned to respond to a sound by performing an action (putting blocks in a box or stacking rings on a stick) [30].

Conventional audiometry has been considered the gold standard for obtaining hearing thresholds between 0.125 to 8 kHz in children of 5 years and older. The child presses a button in response to the sound stimulus. Additionally, the extended high frequencies (EHF) up to 16 kHz may be tested for identification of early ototoxic damage. EHF testing is less widely applied as special calibration of the equipment is required (A.J.M. Meier et al. in press).

#### *2.5.4.3 Objective testing of inner ear status*

For infants up to 6 months of age, behavioural tests are too inaccurate for hearing threshold estimation. To asses hearing of children of this age, objective tests are

**63**

survivors [35].

*Cisplatin Ototoxicity in Children*

middle ear fluid.

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

*2.5.5 Monitoring of ototoxicity in children*

*2.5.5.1 Timing and frequency of testing*

available and widely used in programs for new born hearing screening. These tests can also be used to confirm the outcome of behavioural testing in older children, and may be applied in children/adolescents who are not able to cooperate. A simple and fast way to objectively assess hearing is a test of otoacoustic emissions (OAE), in which a soft probe is placed into the ear canal and the OAE or "cochlear echo" is recorded in response to moderate level clicks or a combination of pure tones delivered via the same probe. OAEs reflect the function of outer hair cells and are only produced in ears with normal hearing or a mild loss of 20–30 dB HL. Presence of an OAE response confirms normal or near-normal hearing. Absence of a response indicates the possibility of a hearing loss and the need for follow-up testing, though it is often due to temporary factors such as excessive head movement or

The main follow-up test in this age group is auditory brainstem response (ABR) testing. Disposable electrodes are attached to the baby's head and rapid clicks or tone pips are delivered to the ear by an insert probe. The electrodes detect field potentials generated by the lower auditory pathways (cochlea and brainstem), producing a characteristic waveform response. The intensity of the stimuli is reduced until the waves are no longer visible, providing a close approximation to behavioural hearing thresholds. When the equipment is well calibrated and click stimuli are used, hearing thresholds around 3 kHz can be estimated, type of hearing loss can be determined (conductive or sensorineural) and integrity of the VIIIth cranial nerve and lower brainstem can be assessed. ABR is preferably measured during sleep, but in some situations sedation must be applied ([30], A.J.M. Meier et al. in press).

As cisplatin-induced ototoxicity in children may have a negative impact on speech-language development and quality of life, early detection of hearing loss by audiological assessments is important. Monitoring during and after cancer therapy facilitates audiological management including counselling of patients and family, and support of hearing function if necessary (hearing aids, assistive listening devices, speech and language therapy) [33]. During therapy, monitoring may also provide the opportunity to modify cisplatin dose, depending highly on the availability of an evidence-based alternative, and whether or not cisplatin is the backbone of treatment. For example, dose adjustment may not be applicable in patients with liver tumours, for whom cisplatin is the key component of survival [34].

A baseline assessment before start of cisplatin treatment, where possible, is important to identify pre-existing hearing loss, and is accompanied by questions on medical history including previous ear and hearing problems, family history, a check for dysmorphic features and presence of tinnitus. The timing of monitoring and the testing schedule during cancer therapy highly depends on the protocol and patient-specific circumstances. Serial assessments can be considered for patients who receive cisplatin, including a check of middle ear and inner ear function, and presence of tinnitus. A post-treatment assessment is used to identify hearing loss or to record progressive changes in hearing status, often performed within three months after cessation of treatment (A.J.M. Meier et al. in press). It may be necessary to continue monitoring up to several years after treatment to detect a delayed onset of hearing loss. Surveillance is advised annually for young survivors, every other year for older children, and every five years for adolescents and young adult

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

available and widely used in programs for new born hearing screening. These tests can also be used to confirm the outcome of behavioural testing in older children, and may be applied in children/adolescents who are not able to cooperate.

A simple and fast way to objectively assess hearing is a test of otoacoustic emissions (OAE), in which a soft probe is placed into the ear canal and the OAE or "cochlear echo" is recorded in response to moderate level clicks or a combination of pure tones delivered via the same probe. OAEs reflect the function of outer hair cells and are only produced in ears with normal hearing or a mild loss of 20–30 dB HL. Presence of an OAE response confirms normal or near-normal hearing. Absence of a response indicates the possibility of a hearing loss and the need for follow-up testing, though it is often due to temporary factors such as excessive head movement or middle ear fluid.

The main follow-up test in this age group is auditory brainstem response (ABR) testing. Disposable electrodes are attached to the baby's head and rapid clicks or tone pips are delivered to the ear by an insert probe. The electrodes detect field potentials generated by the lower auditory pathways (cochlea and brainstem), producing a characteristic waveform response. The intensity of the stimuli is reduced until the waves are no longer visible, providing a close approximation to behavioural hearing thresholds. When the equipment is well calibrated and click stimuli are used, hearing thresholds around 3 kHz can be estimated, type of hearing loss can be determined (conductive or sensorineural) and integrity of the VIIIth cranial nerve and lower brainstem can be assessed. ABR is preferably measured during sleep, but in some situations sedation must be applied ([30], A.J.M. Meier et al. in press).

#### *2.5.5 Monitoring of ototoxicity in children*

As cisplatin-induced ototoxicity in children may have a negative impact on speech-language development and quality of life, early detection of hearing loss by audiological assessments is important. Monitoring during and after cancer therapy facilitates audiological management including counselling of patients and family, and support of hearing function if necessary (hearing aids, assistive listening devices, speech and language therapy) [33]. During therapy, monitoring may also provide the opportunity to modify cisplatin dose, depending highly on the availability of an evidence-based alternative, and whether or not cisplatin is the backbone of treatment. For example, dose adjustment may not be applicable in patients with liver tumours, for whom cisplatin is the key component of survival [34].

#### *2.5.5.1 Timing and frequency of testing*

A baseline assessment before start of cisplatin treatment, where possible, is important to identify pre-existing hearing loss, and is accompanied by questions on medical history including previous ear and hearing problems, family history, a check for dysmorphic features and presence of tinnitus. The timing of monitoring and the testing schedule during cancer therapy highly depends on the protocol and patient-specific circumstances. Serial assessments can be considered for patients who receive cisplatin, including a check of middle ear and inner ear function, and presence of tinnitus. A post-treatment assessment is used to identify hearing loss or to record progressive changes in hearing status, often performed within three months after cessation of treatment (A.J.M. Meier et al. in press). It may be necessary to continue monitoring up to several years after treatment to detect a delayed onset of hearing loss. Surveillance is advised annually for young survivors, every other year for older children, and every five years for adolescents and young adult survivors [35].

#### *2.5.6 Grading of hearing loss in children*

When cisplatin was first used in young children at GOSH there were no appropriate grading scales with which to compare ototoxicity measurements taken from children receiving the same or different treatments including cisplatin. There were the common toxicity criteria of adverse events (CTCAE) and the American Speech-Language Hearing Association (ASHA) criteria, but both compared hearing measured after treatment to baseline hearing. These approaches can be used in older children where baseline hearing can be established. In very young sick children it is difficult to get a reliable baseline and the tests used at a very young age are not the same as the tests used later on. Sue Bellman, the audiologist at the time at GOSH studied the particular pattern of hearing loss which the children were developing. She designed a scale which was published by Brock in 1991 and became known as the Brock grading [7]. Brock grading was later thought not to be sensitive enough and was developed further and a new scale published by Kay Chang in 2010 [36]. There followed a consensus meeting at the annual general meeting of SIOP in Boston and the SIOP scale was introduced and published in 2012 [21]. Grading can be done from the audiogram locally but when comparison of grading is required for the purposes of studying the toxicity of one treatment regimen with another in a clinical trial then central review of audiograms is necessary to assure consistency and quality. This is particularly the case in international clinical trials where the audiogram needs to be uploaded to the trial database for review.

#### *2.5.7 The developmental and psychological impacts of hearing loss*

The developmental and psychological impacts of deafness on children are diverse and substantial. In addition to the primary influence of hearing loss on the acquisition of language and literacy skills, children with any degree of hearing loss are at increased risk of experiencing social, emotional and behavioural difficulties as well as potential influences on quality of life, identity and self-esteem. All these consequences are well documented for children with congenital hearing loss, with research typically focusing on children with severe or profound deafness, and recently, those who have received cochlear implants. Research findings reveal a highly complex picture, with a large number of factors interacting to result in the difficulties presented by any individual child, including for example their language and communication skills, the cause of their deafness, their educational provision, and parental socio-economic status. The picture is somewhat less clear for children who have a mild or moderate hearing loss (often referred to as minimal hearing loss, and the largest group of children affected by ototoxicity), or those who acquired a loss during childhood due to illness directly (for example meningitis), or as in the case of ototoxicity, due to the treatment of illness. However, there is increasingly empirical evidence that is relevant in relation to the developmental and psychological impacts of ototoxicity-induced hearing loss.

The most significant impact of hearing loss is during infancy and early childhood, when language skills are developing at their fastest but delays may go unrecognised or untreated until the child enters school [37]. Thus age of exposure to ototoxic drugs is of particular importance, since even if the hearing loss is confined to the high frequencies, it can have subtle but significant impacts on speech perception and therefore speech production and intelligibility [38, 39]. Audibility and recognition of high-frequency speech sounds (s, f, th, sh, h, k, and t) and perception of fricative phonemes (e. g./s/) supports phonological and morphological development in young children with normal hearing and children with hearing loss [39]. Delays in language development acquired at this time may be hard to reverse, even with appropriate amplification and speech therapy [40].

**65**

*Cisplatin Ototoxicity in Children*

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

levels, higher stress and poorer self-esteem.

A review of the literature on minimal hearing loss (comprising 69 articles, 6 of which included children with high-frequency hearing loss) concluded that although some individuals appeared to have no observable speech-language or academic difficulties, others experience considerable problems [37]. Those children that perform in the normal, average range on tests of language skills and academic attainments may in fact be under-performing in relation to their cognitive potential (IQ ). In addition, children who appear not to have been negatively affected in terms of language and academic development, may still present with significant psychosocial problems. As a group, children with any degree of hearing loss, as well as those specifically with minimal hearing loss, exhibit higher rates of behaviour problems such as noncompliance, aggression, hyperactivity, impulsivity, and inattention than their hearing peers. They also have more emotional problems such as lower energy

The psychosocial impact of hearing loss is also seen in terms of the effect on quality of life. A systematic review of 41 articles [41], showed that children with hearing loss generally report a lower quality of life than their normally-hearing peers. Their meta-analysis on four studies employing the Paediatric Quality of Life Inventory (PedsQL), revealed statistically and clinically significant differences in PedsQL scores between children with normal hearing and those with hearing loss, in the Social and School domains. Recently, a study reported detrimental effects of hearing loss on quality of life in children and adolescents who suffered hearing loss following ototoxic treatment compared with those whose hearing was unaffected [11]. All the areas assessed were impacted, including the ability to communicate with family and peers, level of independence, interactions with peers and emotional well-being. Long-term follow-up of childhood cancer survivors indicates significant hearing loss as predictive of poorer outcomes for school, employment and independent living [42].

As a result of these developmental and psychosocial consequences of ototoxicity-induced hearing loss it is essential that children are not only closely monitored in terms of their hearing thresholds, but also the wider language, learning, social, emotional and behavioural impacts. A range of interventions may be needed, including speech and language therapy, classroom and teaching accommodations and strategies to maximise access to speech and peer interactions, as well as thera-

The Global Initiative for Childhood Cancer (GICC) which was launched in 2018 by the WHO in partnership the International Society of Paediatric Oncology has the goal of improving the Global survival of children with cancer to 60% by 2030. As child cancer services develop and more gain children access cancer care, it will be necessary to develop policy and services to address the long term effects of chance treatment [43]. Cisplatin, is included in the WHO Essential Medicines List for Children (2017), but severe acquired hearing loss in child cancer survivors may have very significant impact on learning and future education opportunities of survivors and increase the health burden in families [44, 45]. Studies from low-and middle-income countries report the prevalence of hearing loss in community screened children as about 10%, while it is 23% for children with co-morbidities, such as HIV, tuberculosis, chronic suppurative otitis media and impacted cerumen% [46, 47]. Adding cisplatin as childhood cancer treatment may therefore increase the prevalence of hearing loss, which increases the need for early identification in the context of limited resources. Community health care workers have been successfully trained to assist and implement screening for hearing loss in communities, which should be used to assist in continuous assessment of hearing in children, surviving childhood cancer after cisplatin treatment and return

peutic interventions to address emotional and behavioural problems.

*2.5.8 Resource challenged nations and cisplatin hearing loss*

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

A review of the literature on minimal hearing loss (comprising 69 articles, 6 of which included children with high-frequency hearing loss) concluded that although some individuals appeared to have no observable speech-language or academic difficulties, others experience considerable problems [37]. Those children that perform in the normal, average range on tests of language skills and academic attainments may in fact be under-performing in relation to their cognitive potential (IQ ). In addition, children who appear not to have been negatively affected in terms of language and academic development, may still present with significant psychosocial problems. As a group, children with any degree of hearing loss, as well as those specifically with minimal hearing loss, exhibit higher rates of behaviour problems such as noncompliance, aggression, hyperactivity, impulsivity, and inattention than their hearing peers. They also have more emotional problems such as lower energy levels, higher stress and poorer self-esteem.

The psychosocial impact of hearing loss is also seen in terms of the effect on quality of life. A systematic review of 41 articles [41], showed that children with hearing loss generally report a lower quality of life than their normally-hearing peers. Their meta-analysis on four studies employing the Paediatric Quality of Life Inventory (PedsQL), revealed statistically and clinically significant differences in PedsQL scores between children with normal hearing and those with hearing loss, in the Social and School domains. Recently, a study reported detrimental effects of hearing loss on quality of life in children and adolescents who suffered hearing loss following ototoxic treatment compared with those whose hearing was unaffected [11]. All the areas assessed were impacted, including the ability to communicate with family and peers, level of independence, interactions with peers and emotional well-being. Long-term follow-up of childhood cancer survivors indicates significant hearing loss as predictive of poorer outcomes for school, employment and independent living [42].

As a result of these developmental and psychosocial consequences of ototoxicity-induced hearing loss it is essential that children are not only closely monitored in terms of their hearing thresholds, but also the wider language, learning, social, emotional and behavioural impacts. A range of interventions may be needed, including speech and language therapy, classroom and teaching accommodations and strategies to maximise access to speech and peer interactions, as well as therapeutic interventions to address emotional and behavioural problems.

#### *2.5.8 Resource challenged nations and cisplatin hearing loss*

The Global Initiative for Childhood Cancer (GICC) which was launched in 2018 by the WHO in partnership the International Society of Paediatric Oncology has the goal of improving the Global survival of children with cancer to 60% by 2030. As child cancer services develop and more gain children access cancer care, it will be necessary to develop policy and services to address the long term effects of chance treatment [43]. Cisplatin, is included in the WHO Essential Medicines List for Children (2017), but severe acquired hearing loss in child cancer survivors may have very significant impact on learning and future education opportunities of survivors and increase the health burden in families [44, 45]. Studies from low-and middle-income countries report the prevalence of hearing loss in community screened children as about 10%, while it is 23% for children with co-morbidities, such as HIV, tuberculosis, chronic suppurative otitis media and impacted cerumen% [46, 47]. Adding cisplatin as childhood cancer treatment may therefore increase the prevalence of hearing loss, which increases the need for early identification in the context of limited resources. Community health care workers have been successfully trained to assist and implement screening for hearing loss in communities, which should be used to assist in continuous assessment of hearing in children, surviving childhood cancer after cisplatin treatment and return to their communities [45]. These identified children should be referred back to the major urban treatment centres for further more sophisticated hearing assessment and management. However, it should be noted that in Sub-Saharan Africa, and in the most populous parts of South East Asia there is a general lack of audiologists and limited access to testing and hearing support, which may hamper rehabilitation. These resource-constricted countries should therefore establish partnerships with developed countries and non-governmental organisations to assist them in the management of childhood cancer survivors with hearing loss due to cisplatin [48].

#### *2.5.9 The parent's perspective*

A parent with a child going through treatment is always trying to find the balance between a desperate longing for their child to be cancer free whilst enduring the least possible short and long-term side effects. At the start of treatment, when doctors explain the risks of potential hearing loss when using cisplatin, it can be hard to fully appreciate and understand the long-term impact for your child. At this stage of treatment many different outcomes are as yet unknown. This is especially true if the child receiving treatment is very young and unable to communicate verbally. The impact of having to wear hearing aids and other assistive listening devices is unknown and therefore almost impossible to comprehend. Whilst going through treatment the support given by doctors and nurses is invaluable. Once treatment ends access to that level of specialised support ends too. Parents are delighted to have a child free from cancer but all too often they are left to deal with the consequences of long-term side effects on their own. This can mean that young children learning to speak, read and write are not given adequate learning support since parents do not always know how best to help them or even what kinds of basic learning support to ask for. At a young age the child will not know in what circumstances they find it difficult to hear and parents need to be aware of every situation in order to be able to help the child develop coping strategies. This is especially true in nursery and primary school settings where a child could quickly feel overwhelmed. It would be easy for that child to be incorrectly labelled as reclusive, of low ability or naughty in class. As the child gets older, they will be able to deal with situations more easily themselves but will easily get tired and quickly zone out. Parents might need to advocate for their child and make the school aware of their needs. Interventions could include sitting at the front of exam halls, increasing teacher awareness in situations like sports pitches, playgrounds, swimming pools and in noisy classrooms. It is easy for a child with hearing loss to retreat from interactions or to become frustrated and then behave poorly. Parents need assistance and information to know how best to help and support their child. Children need to be encouraged to ask for help rather than be singled out or stigmatised.

#### *2.5.10 The search for otoprotectants*

As soon as it was known that cisplatin caused irreversible hearing loss researchers began to look for drugs to protect against this side effect. Different medications have an impact at different points in the metabolism of the cell **Figure 8** [49].

#### *2.5.10.1 Preclinical studies of ototprotectants*

The most promising pre-clinical studies have come from Edward Neuwelt's team in Portland Oregon [50–52]. They have been working on Sodium Thiosulfate (STS) and N-Acetyl Cysteine (NAC). As can be seen in **Figure 8** these 2 drugs can act at different points both inside and outside the cell.

**67**

**Figure 8.**

*jmedchem.7b01653.*

*Cisplatin Ototoxicity in Children*

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

*2.5.10.2 Clinical trials of otoprotectants in children*

**2.6 Cisplatin neurotoxicity**

15 minute infusion given 6 hours after the cisplatin infusion ends.

stopped. In young children neurotoxicity is rarely observed.

**2.7 Hearing conservation from the public health perspective**

In 2019 a clinical guideline paper was written by a multidisciplinary team led by Lillian Sung and David Freyer [15]. The conclusion of this paper was that to date the most promising otoprotectant is STS, see **Table 2** taken from this paper. STS is close to being licenced both in North America and Europe. The evidence for the use of STS in children comes from two phase III trials [53, 54] which both showed that the incidence of hearing loss can be reduced by 50% in children receiving STS as a

*General mechanistic pathways of cisplatin-induced cytotoxicity in auditory cells and the mechanistic pathways by which the otoprotective clinical candidates combat cisplatin toxicity [47]. https://doi.org/10.1021/acs.*

In adults, peripheral sensitive neurotoxicity which ranges from paresthesias to ataxic gait is the dose limiting toxicity of cisplatin [55]. This means that when patients develop severe neurotoxicity the dose of cisplatin needs to be adapted or

Cisplatin hearing loss is considered to worsen with time. It is not clear whether this is due to ongoing toxicity from platinum retained in the cochlea or the addition of further assaults on the ear or both. Hearing educational programs for the young

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

#### **Figure 8.**

*General mechanistic pathways of cisplatin-induced cytotoxicity in auditory cells and the mechanistic pathways by which the otoprotective clinical candidates combat cisplatin toxicity [47]. https://doi.org/10.1021/acs. jmedchem.7b01653.*

#### *2.5.10.2 Clinical trials of otoprotectants in children*

In 2019 a clinical guideline paper was written by a multidisciplinary team led by Lillian Sung and David Freyer [15]. The conclusion of this paper was that to date the most promising otoprotectant is STS, see **Table 2** taken from this paper. STS is close to being licenced both in North America and Europe. The evidence for the use of STS in children comes from two phase III trials [53, 54] which both showed that the incidence of hearing loss can be reduced by 50% in children receiving STS as a 15 minute infusion given 6 hours after the cisplatin infusion ends.

#### **2.6 Cisplatin neurotoxicity**

In adults, peripheral sensitive neurotoxicity which ranges from paresthesias to ataxic gait is the dose limiting toxicity of cisplatin [55]. This means that when patients develop severe neurotoxicity the dose of cisplatin needs to be adapted or stopped. In young children neurotoxicity is rarely observed.

#### **2.7 Hearing conservation from the public health perspective**

Cisplatin hearing loss is considered to worsen with time. It is not clear whether this is due to ongoing toxicity from platinum retained in the cochlea or the addition of further assaults on the ear or both. Hearing educational programs for the young


#### **Table 2.**

*Data synthesis of trials for cisplatin-induced ototoxicity prevention.*

are few and far between [56]. It is clear that children who have received cisplatin as part of their therapy for cancer need to be supported but also educated as they go through follow up to conserve their hearing. It is possible that at the end of treatment ototoxicity damage is not yet apparent to the young person as it may only affect the higher frequencies out of their speech range. With time however as hearing worsens as a result of the toxicity, possibly in interaction with noise induced hearing loss [57], it may reach the speech frequencies and become apparent. Hearing conservation strategies should be introduced to the parents and child at an early stage and should encourage exclusion/reduction of factors which can lead to damage to residual hearing. Not all of these factors can be excluded however it is only fair that parents and patients are made aware of the additional risk to hearing that they bring. These include: loud sounds and noises; other ototoxic medication e.g., aminoglycosides; unhealthy diets; intracranial pressure changes for example as can occur with certain sports such as scuba diving; barotrauma; head injury and exposure to radiation and proton beam therapy. Where possible children and adolescents should be discouraged from listening to loud music through headphones over long periods of time, encouraged to wear protective ear plugs if exposed to loud noise, wear protective head gear when cycling; use a head rest/child safety car seat adjusted to height.

To raise awareness of policy makers to address the problems of preventable hearing loss worldwide, the WHO World Health Assembly adopted a resolution in 2017

**69**

*Cisplatin Ototoxicity in Children*

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

rehabilitation and communication.

them fully socially integrating.

acquire this challenging side effect of treatment.

All other authors have no conflict of interest.

**2.8 Future challenges**

**3. Conclusion**

**Acknowledgements**

research and prevent it.

**Conflict of interest**

(WHA70.13) to provide guidance for member states for the integration of ear and hearing care into national health plans. In response The World Report on Hearing has been developed (https://www.who.int/activities/highlighting-priorities-forear-and-hearing-care), proposing a set of interventions for prevention, screening,

A better understanding of the predisposing genetic factors and how to influence them as well as the introduction of licenced otoprotectants will hopefully reduce the incidence of acquired ototoxicity. In the meantime children who have already developed hearing loss or other ototoxicity need expert support, audiological intervention as well as encouragement, acceptance, patience and tolerance to support

Cisplatin ototoxicity is a serious medical problem in children with cancer whos' cure depends on the use of this drug. Progress has been made on understanding the mechanisms causing the toxicity and some of the predisposing factors. Expert counselling and management of the hearing loss, tinnitus and or vertigo is very important for all children. Understanding and adaptation at home, school and in the work place can facilitate better integration and outcomes for people suffering from acquired toxicity. Otoprotective drugs are being researched to reduce the severity of hearing loss and some will hopefully soon be licenced for use. However further research is needed in all areas to improve the quality of life for children who

We would like to acknowledge Edward Neuwelt and his dedicated team of collaborators for all of the pre-clinical work on both STS. Also to David Freyer, Kristy Knight and Kay Chang for their dedication to the monitoring of late effects and particularly hearing loss in children receiving cisplatin and their efforts to

Penelope Brock has been a consultant with Fennec Pharmaceuticals since 2017.

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

(WHA70.13) to provide guidance for member states for the integration of ear and hearing care into national health plans. In response The World Report on Hearing has been developed (https://www.who.int/activities/highlighting-priorities-forear-and-hearing-care), proposing a set of interventions for prevention, screening, rehabilitation and communication.

#### **2.8 Future challenges**

A better understanding of the predisposing genetic factors and how to influence them as well as the introduction of licenced otoprotectants will hopefully reduce the incidence of acquired ototoxicity. In the meantime children who have already developed hearing loss or other ototoxicity need expert support, audiological intervention as well as encouragement, acceptance, patience and tolerance to support them fully socially integrating.

#### **3. Conclusion**

Cisplatin ototoxicity is a serious medical problem in children with cancer whos' cure depends on the use of this drug. Progress has been made on understanding the mechanisms causing the toxicity and some of the predisposing factors. Expert counselling and management of the hearing loss, tinnitus and or vertigo is very important for all children. Understanding and adaptation at home, school and in the work place can facilitate better integration and outcomes for people suffering from acquired toxicity. Otoprotective drugs are being researched to reduce the severity of hearing loss and some will hopefully soon be licenced for use. However further research is needed in all areas to improve the quality of life for children who acquire this challenging side effect of treatment.

#### **Acknowledgements**

We would like to acknowledge Edward Neuwelt and his dedicated team of collaborators for all of the pre-clinical work on both STS. Also to David Freyer, Kristy Knight and Kay Chang for their dedication to the monitoring of late effects and particularly hearing loss in children receiving cisplatin and their efforts to research and prevent it.

#### **Conflict of interest**

Penelope Brock has been a consultant with Fennec Pharmaceuticals since 2017. All other authors have no conflict of interest.

#### **Author details**

Penelope Brock1 \*, Kaukab Rajput1 , Lindsey Edwards1 , Annelot Meijer2 , Philippa Simpkin3 , Alex Hoetink4 , Mariana Kruger<sup>5</sup> , Michael Sullivan6 and Marry van den Heuvel-Eibrink<sup>2</sup>

1 Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

2 Princess Máxima Centre for Pediatric Oncology, Utrecht, The Netherlands

3 Independent Researcher, London, UK

4 University Medical Centre, Utrecht, The Netherlands

5 Stellenbosch University, South Africa

6 Royal Children's Hospital, Melbourne, Australia

\*Address all correspondence to: peppybrock@gmail.com

© 2021 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.

**71**

*Cisplatin Ototoxicity in Children*

emissions. J Clin Oncol. 2007;

[2] Knight KR, Chen L, Freyer D, Aplenc R, Bancroft M, Bliss B, et al. Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children's Oncology Group. J Clin

[3] Einhorn LH. Chemotherapy of disseminated testicular cancer. Cancer.

[4] The Discovery, Use and Impact of Platinum Salts as Chemotherapy Agents for Cancer The transcript of a Witness Seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 4 April 2006 [Internet]. Available from: https://discovery.ucl.ac.uk/id/

eprint/14884/1/14884.pdf

Pediatr. 1991;

Health. 2010.

Oncol. 1991;

[5] Brock PR, Koliouskas DE, Barratt TM, Yeomans E, Pritchard J. Partial reversibility of cisplatin nephrotoxicity in children. J

[6] Skinner R. Nephrotoxicity of cancer treatment in children. Pediatric

[8] Oeffinger KC, Mertens AC,

Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic Health

[7] Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: A practical grading system. Med Pediatr

**References**

Oncol. 2017;

1980;20(3):625-629.

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

[1] Knight KR, Kraemer DP, Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: Use of extended high-frequency audiometry and evoked distortion product otoacoustic

Conditions in Adult Survivors of Childhood Cancer. N Engl J Med. 2006;

[9] Clemens E, de Vries ACH, am Zehnhoff-Dinnesen A, Tissing WJE, Loonen JJ, Pluijm SFM, et al. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors. Pediatr

[10] Clemens E, Broer L, Langer T, Uitterlinden AG, de Vries ACH, van Grotel M, et al. Genetic variation of cisplatin-induced ototoxicity in noncranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study. Pharmacogenomics J. 2020;

[11] Rajput K, Edwards L, Brock P, Abiodun A, Simpkin P, Al-Malky G. Ototoxicity-induced hearing loss and quality of life in survivors of paediatric cancer. Vol. 138, International Journal of Pediatric Otorhinolaryngology. 2020.

[12] Childhood Cancer PFDD [Internet]. Childhood Cancer Hearing Loss. An externally-led public-focused drug development workshop: Chemotherapyinduced hearing loss in pediatric oncology. Available from: www. childhoodcancerpfdd.org

[13] Kushner BH, Budnick A, Kramer K, Modak S, Cheung NK V. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006;

[14] Freyer DR, Brock P, Knight K, Reaman G, Cabral S, Robinson PD, et al. Interventions for cisplatin-induced hearing loss in children and adolescents with cancer. The Lancet Child and

[15] Freyer DR, Brock PR, Chang KW, Dupuis LL, Epelman S, Knight K, et al. Prevention of cisplatin-induced

Adolescent Health. 2019.

Hematol Oncol. 2017;

*Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

#### **References**

[1] Knight KR, Kraemer DP, Winter C, Neuwelt EA. Early changes in auditory function as a result of platinum chemotherapy: Use of extended high-frequency audiometry and evoked distortion product otoacoustic emissions. J Clin Oncol. 2007;

[2] Knight KR, Chen L, Freyer D, Aplenc R, Bancroft M, Bliss B, et al. Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children's Oncology Group. J Clin Oncol. 2017;

[3] Einhorn LH. Chemotherapy of disseminated testicular cancer. Cancer. 1980;20(3):625-629.

[4] The Discovery, Use and Impact of Platinum Salts as Chemotherapy Agents for Cancer The transcript of a Witness Seminar held by the Wellcome Trust Centre for the History of Medicine at UCL, London, on 4 April 2006 [Internet]. Available from: https://discovery.ucl.ac.uk/id/ eprint/14884/1/14884.pdf

[5] Brock PR, Koliouskas DE, Barratt TM, Yeomans E, Pritchard J. Partial reversibility of cisplatin nephrotoxicity in children. J Pediatr. 1991;

[6] Skinner R. Nephrotoxicity of cancer treatment in children. Pediatric Health. 2010.

[7] Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: A practical grading system. Med Pediatr Oncol. 1991;

[8] Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic Health

Conditions in Adult Survivors of Childhood Cancer. N Engl J Med. 2006;

[9] Clemens E, de Vries ACH, am Zehnhoff-Dinnesen A, Tissing WJE, Loonen JJ, Pluijm SFM, et al. Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors. Pediatr Hematol Oncol. 2017;

[10] Clemens E, Broer L, Langer T, Uitterlinden AG, de Vries ACH, van Grotel M, et al. Genetic variation of cisplatin-induced ototoxicity in noncranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study. Pharmacogenomics J. 2020;

[11] Rajput K, Edwards L, Brock P, Abiodun A, Simpkin P, Al-Malky G. Ototoxicity-induced hearing loss and quality of life in survivors of paediatric cancer. Vol. 138, International Journal of Pediatric Otorhinolaryngology. 2020.

[12] Childhood Cancer PFDD [Internet]. Childhood Cancer Hearing Loss. An externally-led public-focused drug development workshop: Chemotherapyinduced hearing loss in pediatric oncology. Available from: www. childhoodcancerpfdd.org

[13] Kushner BH, Budnick A, Kramer K, Modak S, Cheung NK V. Ototoxicity from high-dose use of platinum compounds in patients with neuroblastoma. Cancer. 2006;

[14] Freyer DR, Brock P, Knight K, Reaman G, Cabral S, Robinson PD, et al. Interventions for cisplatin-induced hearing loss in children and adolescents with cancer. The Lancet Child and Adolescent Health. 2019.

[15] Freyer DR, Brock PR, Chang KW, Dupuis LL, Epelman S, Knight K, et al. Prevention of cisplatin-induced

ototoxicity in children and adolescents with cancer: a clinical practice guideline. Lancet Child Adolesc Heal [Internet]. 2020;4(2):141-150. Available from: http://dx.doi.org/10.1016/ S2352-4642(19)30336-0

[16] Clemens E, van der Kooi ALF, Broer L, van Dulmen-den Broeder E, Visscher H, Kremer L, et al. The influence of genetic variation on late toxicities in childhood cancer survivors: A review. Critical Reviews in Oncology/ Hematology. 2018.

[17] Langer T, Clemens E, Broer L, Maier L, Uitterlinden AG, de Vries ACH, et al. Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinuminduced ototoxicity: Results of the European PanCareLIFE cohort study. Eur J Cancer. 2020;138.

[18] Mukherjea D, Rybak LP. Pharmacogenomics of cisplatin-induced ototoxicity. Pharmacogenomics. 2011.

[19] Dolan ME, Newbold KG, Nagasubramanian R, Wu X, Ratain MJ, Cook EH, et al. Heritability and linkage analysis of sensitivity to cisplatininduced cytotoxicity. Cancer Res. 2004;

[20] Brock P, Brichard B, Rechnitzer C, Langeveld NE, Lanning M, Söderhäll S, et al. An increased loading dose of ondansetron: A north European, doubleblind randomised study in children, comparing 5 mg/m2 with 18 mg/m2. Eur J Cancer Part A. 1996;

[21] Brock PR, Knight KR, Freyer DR, Campbell KCM, Steyger PS, Blakley BW, et al. Platinum-induced ototoxicity in children: A consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012;30(19):2408-2417.

[22] Nyberg S, Abbott NJ, Shi X, Steyger PS, Dabdoub A. Delivery of therapeutics to the inner ear : The challenge of the blood-labyrinth barrier. 2019;0935(March):1-12.

[23] Shi X. Pathophysiology of the cochlear intrastrial fluid-blood barrier. Hear Res. 2016;338:52-63.

[24] Breglio AM, Rusheen AE, Shide ED, Fernandez KA, Spielbauer KK, McLachlin KM, et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat Commun [Internet]. 2017;8(1). Available from: http://dx.doi.org/10.1038/ s41467-017-01837-1

[25] Sheth S, Mukherjea D, Rybak LP, Ramkumar V. Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. Front Cell Neurosci. 2017;11(October):1-12.

[26] Ratain MJ, Cox NJ, Henderson TO. Challenges in interpreting the evidence for genetic predictors of ototoxicity. Clinical Pharmacology and Therapeutics. 2013.

[27] Boddy AV. Genetics of cisplatin ototoxicity: confirming the unexplained? Clin Pharmacol Ther. 2013;94(2):198-200.

[28] Clemens E, Brooks B, De Vries ACH, van Grotel M, van den Heuvel-Eibrink MM, Carleton B. A comparison of the Muenster, SIOP Boston, Brock, Chang and CTCAEv4.03 ototoxicity grading scales applied to 3,799 audiograms of childhood cancer patients treated with platinumbased chemotherapy. PLoS One. 2019;14(2):1-15.

[29] Drögemöller BI, Wright GEB, Lo C, Le T, Brooks B, Bhavsar AP, et al. Pharmacogenomics of Cisplatin-Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research. Clinical Pharmacology and Therapeutics. 2019.

**73**

*Cisplatin Ototoxicity in Children*

Otol. 2016;

Audiol. 2018;

*DOI: http://dx.doi.org/10.5772/intechopen.96744*

[30] Sabo DL. The audiologic assessment of the young pediatric patient: The clinic. Trends in Amplification. 1999.

receiving platinum chemotherapy: Underestimating a commonly occurring toxicity that may influence academic and social development. J Clin

[39] Spratford M, McLean HH MR. Relationship of grammatical context on children's recognition of s/zinflected words. J Am Acad Audiol.

[40] Tomblin JB, Harrison M, Ambrose SE, Walker EA, Oleson JJ, Moeller MP. Language outcomes in young children with mild to severe hearing loss. Ear Hear. 2015;

[41] Roland L, Fischer C, Tran K, Rachakonda T, Kallogjeri D, Lieu JEC. Quality of Life in Children with Hearing Impairment: Systematic Review and Meta-analysis. In: Otolaryngology - Head and Neck Surgery (United

[42] Brinkman TM, Bass JK, Li Z, Ness KK, Gajjar A, Pappo AS, et al. Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer.

[43] WHO. WHO Global Initiative for Childhood cancer. [Internet]. Available from: https://siop-online.org/whoglobal-initiative-for-childhood-cancer/

[44] WHO. WHO model list of essential medicines - 21st list, 2019: page 28. [Internet]. Available from: https:// www.who.int/publications/i/item/ WHOMVPEMPIAU2019.06.

Winters N, Chadha S, Bhutta MF. The role of community health workers in addressing the global burden of ear disease and hearing loss: A systematic scoping review of the literature. BMJ

[45] O'Donovan J, Verkerk M,

Glob Heal. 2019;

2015;121(22):4053-4061.

Oncol. 2005;

2017;28(799-809).

States). 2016.

[31] Ting CS, Huang KW, Tzeng YC. Correlation between video-otoscopic images and tympanograms of patients with acute middle ear infection. Indian J

[32] IntechOpen Book Update on Hearing Loss Chapter Classification of Hearing Loss [Internet]. Available from: https://www.intechopen. com/books/update-on-hearing-loss/

classification-of-hearing-loss

[33] Maru D, Malky G Al. Current practice of ototoxicity management across the United Kingdom (UK). Int J

[34] Aronson DC, Czauderna P, Maibach R, Perilongo G, Morland B. The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. Journal of Indian Association of Pediatric Surgeons. 2014.

[35] Clemens E, van den Heuvel-

Hudson MM, Skinner R, et al. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium. The

Lancet Oncology. 2019.

of Clinical Oncology. 2010.

2016;25(3):232-245.

[37] Winiger AM, Alexander JM DA. Minimal hearing loss: From a failure-based approach to evidencebased practice. Am J Audiol.

[38] Knight KRG, Kraemer DF, Neuwelt EA. Ototoxicity in children

Eibrink MM, Mulder RL, Kremer LCM,

[36] Chang KW, Chinosornvatana N. Practical grading system for evaluating cisplatin ototoxicity in children. Journal

#### *Cisplatin Ototoxicity in Children DOI: http://dx.doi.org/10.5772/intechopen.96744*

[30] Sabo DL. The audiologic assessment of the young pediatric patient: The clinic. Trends in Amplification. 1999.

[31] Ting CS, Huang KW, Tzeng YC. Correlation between video-otoscopic images and tympanograms of patients with acute middle ear infection. Indian J Otol. 2016;

[32] IntechOpen Book Update on Hearing Loss Chapter Classification of Hearing Loss [Internet]. Available from: https://www.intechopen. com/books/update-on-hearing-loss/ classification-of-hearing-loss

[33] Maru D, Malky G Al. Current practice of ototoxicity management across the United Kingdom (UK). Int J Audiol. 2018;

[34] Aronson DC, Czauderna P, Maibach R, Perilongo G, Morland B. The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. Journal of Indian Association of Pediatric Surgeons. 2014.

[35] Clemens E, van den Heuvel-Eibrink MM, Mulder RL, Kremer LCM, Hudson MM, Skinner R, et al. Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium. The Lancet Oncology. 2019.

[36] Chang KW, Chinosornvatana N. Practical grading system for evaluating cisplatin ototoxicity in children. Journal of Clinical Oncology. 2010.

[37] Winiger AM, Alexander JM DA. Minimal hearing loss: From a failure-based approach to evidencebased practice. Am J Audiol. 2016;25(3):232-245.

[38] Knight KRG, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: Underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol. 2005;

[39] Spratford M, McLean HH MR. Relationship of grammatical context on children's recognition of s/zinflected words. J Am Acad Audiol. 2017;28(799-809).

[40] Tomblin JB, Harrison M, Ambrose SE, Walker EA, Oleson JJ, Moeller MP. Language outcomes in young children with mild to severe hearing loss. Ear Hear. 2015;

[41] Roland L, Fischer C, Tran K, Rachakonda T, Kallogjeri D, Lieu JEC. Quality of Life in Children with Hearing Impairment: Systematic Review and Meta-analysis. In: Otolaryngology - Head and Neck Surgery (United States). 2016.

[42] Brinkman TM, Bass JK, Li Z, Ness KK, Gajjar A, Pappo AS, et al. Treatment-induced hearing loss and adult social outcomes in survivors of childhood CNS and non-CNS solid tumors: Results from the St. Jude Lifetime Cohort Study. Cancer. 2015;121(22):4053-4061.

[43] WHO. WHO Global Initiative for Childhood cancer. [Internet]. Available from: https://siop-online.org/whoglobal-initiative-for-childhood-cancer/

[44] WHO. WHO model list of essential medicines - 21st list, 2019: page 28. [Internet]. Available from: https:// www.who.int/publications/i/item/ WHOMVPEMPIAU2019.06.

[45] O'Donovan J, Verkerk M, Winters N, Chadha S, Bhutta MF. The role of community health workers in addressing the global burden of ear disease and hearing loss: A systematic scoping review of the literature. BMJ Glob Heal. 2019;

[46] Mulwafu W, Kuper H, Ensink RJH. Prevalence and causes of hearing impairment in Africa. Tropical Medicine and International Health. 2016.

[47] Leach AJ, Homøe P, Chidziva C, Gunasekera H, Kong K, Bhutta MF, et al. Panel 6: Otitis media and associated hearing loss among disadvantaged populations and low to middleincome countries. Int J Pediatr Otorhinolaryngol. 2020;

[48] Mulwafu W, Ensink R, Kuper H, Fagan J. Survey of ENT services in sub-Saharan Africa: Little progress between 2009 and 2015. Glob Health Action. 2017;

[49] Hazlitt RA, Min J, Zuo J. Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss. J Med Chem. 2018;61(13):5512-5524.

[50] Neuwelt EA, Brummett RE, Doolittle ND, Muldoon LL, Kroll RA, Pagel MA, et al. First evidence of otoprotection against carboplatininduced hearing loss with a twocompartment system in patients with central nervous system malignancy using sodium thiosulfate. J Pharmacol Exp Ther. 1998;

[51] Doolittle ND, Muldoon LL, Brummett RE, Tyson RM, Lacy C, Bubalo JS, et al. Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors. Clin Cancer Res. 2001;

[52] Doolittle ND, Peereboom DM, Christoforidis GA, Hall WA, Palmieri D, Brock PR, et al. Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumors: Report of the eleventh annual bloodbrain barrier consortium meeting. J Neurooncol. 2007;

[53] Freyer DR, Chen L, Krailo MD, Knight K, Villaluna D, Bliss B, et al. Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2017;

[54] Brock PR, Maibach R, Childs M, Rajput K, Roebuck D, Sullivan MJ, et al. Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med. 2018;

[55] Avan A, Postma TJ, Ceresa C, Avan A, Cavaletti G, Giovannetti E, et al. Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future. Oncologist. 2015;

[56] Khan KM, Bielko SL, Mccullagh MC. Efficacy of hearing conservation education programs for youth and young adults : a systematic review. BMC Public Health. 2018;18.

[57] Yang C, Schrepfer T, Schacht J. Age-related hearing impairment and the triad of acquired hearing loss. 2015;9(July):1-12.

**75**

Section 3

Teamwork Approach

to Hearing Loss

Comorbidities

Section 3

 Teamwork Approach to Hearing Loss Comorbidities

**77**

acquired [1].

**Chapter 6**

**Abstract**

Oto-renal syndrome

**1. Introduction**

**1.1 Structure and function of the ear**

Corti cause toxic damage to it (ototoxicity).

**1.2 The kidney and the inner ear (labyrinth)**

organs, including the inner ear, to function optimally.

Disease

Hearing Loss in Chronic Kidney

Chronic kidney disease (CKD) is assuming public health significance worldwide

largely driven by the surge in diabetes mellitus, hypertension and obesity. CKD patients, particularly those from resource restraint regions of the world, face huge challenge in terms of accessibility and affordability to care. Besides these challenges in care, several other co-morbidities often exist among these patients in addition to the primary disease like diabetes and hypertension. Yet, these "subtle" co-morbidities are often overlooked by Caregivers. Hearing loss is one of such co-morbidities CKD patients face but it is often overlooked. The situation is worse among children who often cannot express themselves. The etiology of hearing loss among CKD patients are multifactorial. It is hoped that this neglected aspect of care for patients with chronic kidney disease will receive the needed attention for holistic care of the CKD patient.

**Keywords:** chronic kidney disease, co-morbidity, hearing loss, aetiopathogenesis,

The ear is the organ for hearing. The human ear consists of three parts: 1. the external ear 2. the middle ear 3. the inner ear. The inner ear, also called the labyrinth, consists of the vestibular apparatus for balance; and the cochlear for hearing. The external and middle ear portions of this hearing apparatus are responsible for conducting sound energy from the exterior and transforming it into mechanical energy towards the inner ear. The inner ear then converts the received mechanical energy into electrical energy. The cochlear component of the inner ear is the end-organ for hearing. The organ of Corti within the cochlear is the functional processing unit for hearing aspect of the inner ear. This organ is very sensitive to the chemical environment. Changes in the physiological environment of the organ of

Variety of factors contribute to functional deterioration of the inner ear. These include aging, chemicals, medications and certain diseases both congenital and

The kidney is the organ primarily responsible for the elimination of toxic metabolites from the body and thereby creating the required milieu for the internal

*Sampson Antwi and Mohammed Duah Issahalq*

#### **Chapter 6**

## Hearing Loss in Chronic Kidney Disease

*Sampson Antwi and Mohammed Duah Issahalq*

#### **Abstract**

Chronic kidney disease (CKD) is assuming public health significance worldwide largely driven by the surge in diabetes mellitus, hypertension and obesity. CKD patients, particularly those from resource restraint regions of the world, face huge challenge in terms of accessibility and affordability to care. Besides these challenges in care, several other co-morbidities often exist among these patients in addition to the primary disease like diabetes and hypertension. Yet, these "subtle" co-morbidities are often overlooked by Caregivers. Hearing loss is one of such co-morbidities CKD patients face but it is often overlooked. The situation is worse among children who often cannot express themselves. The etiology of hearing loss among CKD patients are multifactorial. It is hoped that this neglected aspect of care for patients with chronic kidney disease will receive the needed attention for holistic care of the CKD patient.

**Keywords:** chronic kidney disease, co-morbidity, hearing loss, aetiopathogenesis, Oto-renal syndrome

#### **1. Introduction**

#### **1.1 Structure and function of the ear**

The ear is the organ for hearing. The human ear consists of three parts: 1. the external ear 2. the middle ear 3. the inner ear. The inner ear, also called the labyrinth, consists of the vestibular apparatus for balance; and the cochlear for hearing.

The external and middle ear portions of this hearing apparatus are responsible for conducting sound energy from the exterior and transforming it into mechanical energy towards the inner ear. The inner ear then converts the received mechanical energy into electrical energy. The cochlear component of the inner ear is the end-organ for hearing. The organ of Corti within the cochlear is the functional processing unit for hearing aspect of the inner ear. This organ is very sensitive to the chemical environment. Changes in the physiological environment of the organ of Corti cause toxic damage to it (ototoxicity).

Variety of factors contribute to functional deterioration of the inner ear. These include aging, chemicals, medications and certain diseases both congenital and acquired [1].

#### **1.2 The kidney and the inner ear (labyrinth)**

The kidney is the organ primarily responsible for the elimination of toxic metabolites from the body and thereby creating the required milieu for the internal organs, including the inner ear, to function optimally.

#### **Figure 1.**

*ClC-K channels are expressed in kidney and inner ear. (A) At the nephrons, luminal NKCC2 transporters build up Na+ , K+ and Cl− into the cells. K+ flows back to the lumen through ROMK1 channels; Na<sup>+</sup> and Cl− are reabsorbed to the bloodstream separately through Na+/K+ ATPase and ClC-kb channels, respectively. (B) In the Stria Vascularis, Na<sup>+</sup> , K+ and Cl− are transported into the cells by basolateral NKCC1 transporters. Na+ and Cl− are recycled back to the interstitium by Na+/K+ ATPase and both ClC-Ks isomers, respectively. K+ flows through KCNQ1/KCNE1 channels and accumulates into the endolymph, a condition required for sensory transduction in inner hair cells. Figure courtesy Poroca DR et al. [4].*

Diseases of the kidney have detrimental effect on the inner ear, not only because of buildup of metabolic toxins in the blood to affect the functions of the labyrinth, but also the fact that the functional unit of the kidney, the nephron, has structural and functional similarities with the stria vascularis in the labyrinth [2, 3]. These similarities make both organs vulnerable to similar agents and genetic disruptions in utero [2, 3].

#### *1.2.1 Ion channels and transporters expressed in both the inner ear and kidney*

ClC proteins are a large family of proteins that mediate voltage-dependent transport of Cl − ions across cell membranes [4]. They are controlled by the CLC gene family. They comprise the CLC-K channels, Cl − channels and Cl−/H+ antiporters. A critical subunit of the CLC-K channels is the protein barttin. These channels and transporters are expressed in both the inner ear and the kidney. [4–6] (**Figure 1**).

The CLC-K channels form homodimers which additionally co-assemble with the small protein barttin. ClC-K/barttin localizes at the basolateral membranes of both the thin and thick ascending limbs of Henle's loop, and in marginal cells of the stria vascularis of the inner ear [5]. In the kidney, they are involved in NaCl reabsorption; in the inner ear they are important for endolymph production (see 2.1.1.3 below).

#### **2. Hearing loss in chronic kidney diseases**

The kidney and the inner ear both suffer from the adverse effects of diseases like diabetes mellitus, hypertension and aging.

**79**

diagnosis.

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

increase in hearing threshold (p-value <0.01) [7].

side effects [9, 12–14].

*2.1.1.1 Hereditary nephritis*

*2.1.1 Genetic causes*

Several reports have indicated that hearing loss is more prevalent among CKD patients than the general population in different parts of the world [7–11]. In a Korean study by Seo1 JY et al. involving 5,226 participants ≥19 years of age whose estimated glomerular filtration rate (eGFR) and hearing threshold were measured, the authors found the odds of hearing impairment to be 1.25 times higher (95% confidence interval: 1.12–1.64, p-value <0.001) in participants with an eGFR <60 mL/min/1.73 m2 (chronic renal failure group) than in those with an eGFR ≥60 mL/min/1.73 m2 (normal or mildly impaired renal function group) after adjustments for age, sex, smoking, alcohol, body mass index, diabetes mellitus, hypertension, dyslipidemia, and microalbuminuria [7]. Among the risk parameters of CKD associated with hearing impairment, linear regression analysis adjusted for age and sex determined that each increase of serum creatinine or blood pressure was positively associated with an

**2.1 Etiology of hearing loss among patients with chronic kidney disease**

The causes of hearing loss among patients with chronic kidney disease are multifactorial, ranging from genetics through uraemic complications to medication

Hereditary nephritis (Alport's syndrome) is a recognized cause of CKD among adolescents and young adults. Alport's syndrome is characterized by progressive kidney failure (mainly from second decade), sensorineural hearing loss and characteristic ocular findings. Cecil Alport first described the disease as hereditary haematuric nephritis with hearing loss in a family whose affected males died in adolescence [15]. The disease is caused by a defect in the gene that codes for basement membrane type IV collagen [15]. The consequence of this genetic defect is a thickened and often split basement membrane giving a characteristic "basket weave" pattern. The disease has variable pattern of inheritance but 85% of cases are X-linked and most or all of those results from mutation of COL4A5, the gene located on chromosome Xq22 that codes for the α5-chainof type IV collagen. Autosomal-recessive inheritance occurs in perhaps 15% of cases, and autosomal-dominant inheritance has been shown in a few cases with associated thrombocytopathy and in rare cases without platelet defects [15]. The disease initially manifests as asymptomatic microscopic haematuria, sometimes with superimposed episodes of gross haematuria. Progressively worsening proteinuria and end stage renal disease (ESRD) may eventually develop, although the rate of progression is quite variable [15].

Affected individuals have bilateral high-frequency sensorineural hearing loss [15]. Nonetheless, some affected individuals with the X-linked nephritis progressing to ESRD may be without hearing loss, an occurrence which might lead to missed

In Alport's syndrome, the similarities in connective tissue structure (collagen type IV) between basement membranes of glomeruli and the stria vascularis of the

In Branchio-Oto-Renal (BOR) syndrome, there is concurrent occurrence of ear and renal abnormalities. Renal abnormalities include bilateral renal agenesis,

inner ear account for the affectation of both organs in most cases [15, 16].

*2.1.1.2 Branchio-Oto-renal (BOR) syndrome*

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

Diseases of the kidney have detrimental effect on the inner ear, not only because of buildup of metabolic toxins in the blood to affect the functions of the labyrinth, but also the fact that the functional unit of the kidney, the nephron, has structural and functional similarities with the stria vascularis in the labyrinth [2, 3]. These similarities make both organs vulnerable to similar agents and genetic disruptions

 *are recycled back to the interstitium by Na+/K+ ATPase and both ClC-Ks isomers, respectively. K+ flows through KCNQ1/KCNE1 channels and accumulates into the endolymph, a condition required for sensory* 

 *flows back to the lumen through ROMK1 channels; Na+*

 *are transported into the cells by basolateral NKCC1 transporters. Na+*

 *and Cl−*

 *are* 

*ClC-K channels are expressed in kidney and inner ear. (A) At the nephrons, luminal NKCC2 transporters* 

*reabsorbed to the bloodstream separately through Na+/K+ ATPase and ClC-kb channels, respectively. (B) In* 

ClC proteins are a large family of proteins that mediate voltage-dependent transport of Cl − ions across cell membranes [4]. They are controlled by the CLC gene family. They comprise the CLC-K channels, Cl − channels and Cl−/H+ antiporters. A critical subunit of the CLC-K channels is the protein barttin. These channels and transporters are expressed in both the inner ear and the kidney. [4–6] (**Figure 1**). The CLC-K channels form homodimers which additionally co-assemble with the small protein barttin. ClC-K/barttin localizes at the basolateral membranes of both the thin and thick ascending limbs of Henle's loop, and in marginal cells of the stria vascularis of the inner ear [5]. In the kidney, they are involved in NaCl reabsorption; in the inner ear they are important for endolymph production

The kidney and the inner ear both suffer from the adverse effects of diseases like

*1.2.1 Ion channels and transporters expressed in both the inner ear and kidney*

**78**

in utero [2, 3].

**Figure 1.**

*and Cl−*

*build up Na+*

*, K+*

*the Stria Vascularis, Na<sup>+</sup>*

 *and Cl−*

*, K+*

 *into the cells. K+*

 *and Cl−*

*transduction in inner hair cells. Figure courtesy Poroca DR et al. [4].*

(see 2.1.1.3 below).

**2. Hearing loss in chronic kidney diseases**

diabetes mellitus, hypertension and aging.

Several reports have indicated that hearing loss is more prevalent among CKD patients than the general population in different parts of the world [7–11]. In a Korean study by Seo1 JY et al. involving 5,226 participants ≥19 years of age whose estimated glomerular filtration rate (eGFR) and hearing threshold were measured, the authors found the odds of hearing impairment to be 1.25 times higher (95% confidence interval: 1.12–1.64, p-value <0.001) in participants with an eGFR <60 mL/min/1.73 m2 (chronic renal failure group) than in those with an eGFR ≥60 mL/min/1.73 m2 (normal or mildly impaired renal function group) after adjustments for age, sex, smoking, alcohol, body mass index, diabetes mellitus, hypertension, dyslipidemia, and microalbuminuria [7]. Among the risk parameters of CKD associated with hearing impairment, linear regression analysis adjusted for age and sex determined that each increase of serum creatinine or blood pressure was positively associated with an increase in hearing threshold (p-value <0.01) [7].

#### **2.1 Etiology of hearing loss among patients with chronic kidney disease**

The causes of hearing loss among patients with chronic kidney disease are multifactorial, ranging from genetics through uraemic complications to medication side effects [9, 12–14].

#### *2.1.1 Genetic causes*

#### *2.1.1.1 Hereditary nephritis*

Hereditary nephritis (Alport's syndrome) is a recognized cause of CKD among adolescents and young adults. Alport's syndrome is characterized by progressive kidney failure (mainly from second decade), sensorineural hearing loss and characteristic ocular findings. Cecil Alport first described the disease as hereditary haematuric nephritis with hearing loss in a family whose affected males died in adolescence [15]. The disease is caused by a defect in the gene that codes for basement membrane type IV collagen [15]. The consequence of this genetic defect is a thickened and often split basement membrane giving a characteristic "basket weave" pattern. The disease has variable pattern of inheritance but 85% of cases are X-linked and most or all of those results from mutation of COL4A5, the gene located on chromosome Xq22 that codes for the α5-chainof type IV collagen. Autosomal-recessive inheritance occurs in perhaps 15% of cases, and autosomal-dominant inheritance has been shown in a few cases with associated thrombocytopathy and in rare cases without platelet defects [15]. The disease initially manifests as asymptomatic microscopic haematuria, sometimes with superimposed episodes of gross haematuria. Progressively worsening proteinuria and end stage renal disease (ESRD) may eventually develop, although the rate of progression is quite variable [15].

Affected individuals have bilateral high-frequency sensorineural hearing loss [15]. Nonetheless, some affected individuals with the X-linked nephritis progressing to ESRD may be without hearing loss, an occurrence which might lead to missed diagnosis.

In Alport's syndrome, the similarities in connective tissue structure (collagen type IV) between basement membranes of glomeruli and the stria vascularis of the inner ear account for the affectation of both organs in most cases [15, 16].

#### *2.1.1.2 Branchio-Oto-renal (BOR) syndrome*

In Branchio-Oto-Renal (BOR) syndrome, there is concurrent occurrence of ear and renal abnormalities. Renal abnormalities include bilateral renal agenesis, bilateral hypoplasia or dysplasia, unilateral renal agenesis with contralateral hypoplasia or dysplasia, ureteropelvic obstruction, and vesicoureteric reflux. Renal function ranges from normal to severe reduction in glomerular filtration rate [17]. The ear abnormalities range from preauricular pits, malformations in the external, middle, and inner ear; and hearing loss [7, 17].

#### *2.1.1.3 ClC-K in renal salt loss and deafness (Bartter syndrome type IV)*

ClC-Kb/barttin (see **Figure 1**) is mainly expressed in basolateral membranes of the thick ascending limb of Henle's loop, where it is involved in the reabsorption of salt and, consequently, water [18]. In this part of the nephron, the Na + electrochemical gradient (created by basolateral Na+/K+ pump) drives the secondary active transport of NKCC2 (present in the apical membrane), accumulating Na+, Cl−, and K+ into the cell. K+ is extruded back to the lumen through ROMK K+ channels (also present in the apical membrane), whereas Na + and Cl − are reabsorbed by the interstitial fluid through the Na+/K+ pump and ClC-Kb channels, respectively. Thus, the end product of this system is the reabsorption of NaCl into the blood stream (**Figure 1A**). In the inner ear, both ClC-K isomers are expressed in the basolateral membrane of marginal cells of the stria vascularis. This multilayered epithelium is responsible for both the high concentration of K+ and the positive potential (about 100 mV higher than normal extracellular fluids) of the endolymph of the scala media, both of which are important properties for hearing. In marginal cells—the more apical layer in the stria vascularis—Na+/K+ pumps and NKCC1 transporters build up K+ and Cl − inside the cells. ClC-K/barttin channels recycle Cl − back to the interstitial fluid, while apical KCNQ1/KCNE1 K+ channels secrete the excess of potassium ions into the endolymph (**Figure 1B**) [19]. In agreement with the transport models involving ClCK/barttin channels, mutations in the gene encoding ClC-Kb cause salt-losing Bartter syndrome type III [20], characterized by hypokalemia, metabolic alkalosis and secondary hyperaldosteronism with normal or low blood pressure [21]. Mutations in the gene encoding barttin cause Bartter syndrome type IV that combines the salt wasting with congenital deafness, since both ClC-K proteins are non-functional in the absence of barttin [22]. When disruption occurs in only one of the ClC-K channels, as it does in ClCKb mutations in Bartter type III, hearing is preserved; the other isomer channel still provides the necessary Cl − recycling. Deafness occurs only on disruption of both ClC-K channels or upon disruption of barttin [22, 23].

#### **2.2 Medication toxic effect**

Over 450 medicines are reported to be ototoxic [24]. These include both prescription medicines such as antibiotics, cancer medications, anti-malarias, and diuretics; and over-the counter medicines such as Non-Steroidal Anti-Inflammatory drugs (Pain killers). In most cases, this type of ototoxicity is an acute, short-lived side effect; if the patient stops taking the medication, the symptoms typically recede [24]. This is not the case, however, for aminoglycoside antibiotics and platinum derivatives used as cancer drugs which may be associated with permanent hearing loss [25]. The mechanism of drug-induced ototoxicity is varied.

#### *2.2.1 Aminoglycoside antibiotics and high-ceiling diuretics*

For the patient with CKD, the medications of importance in causing ototoxicity are the aminoglycoside antibiotics, used commonly in treating urinary tract infections and septicaemia which are quite frequent in such patients and also

**81**

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

take away the interest in evaluation for this side effect.

intravenous push medication and in a faster fashion.

another cohort of CKD patient who suffer from hearing loss.

**2.3 Hearing loss among hemodialysis patients**

population. It ranges from 28% to 77% [26, 27].

mellitus and hypertension, and hemodialysis [31–33].

the glomeruli in the kidney [3].

CRF [30].

furosemide; a high-ceiling diuretic commonly used in treating fluid overload and pulmonary oedema in CKD patients. Though the ototoxic effect of aminoglycoside is known among many medical practitioners, the lack of diagnostic facilities in many centers across the world lead to the neglect of full assessment for this potential side effect. Lack of treatment interventions for hearing loss in many regions

The ototoxicity of furosemide is often overlooked by physicians and nurses. Furosemide toxicity commonly occurs when the medicine is administered as

Chronic kidney disease patients in End stage who are on hemodialysis are

Several reports indicate that sensorineural hearing loss (SNHL) is considerably more prevalent in patients with chronic renal failure (CRF) than in the general

Although all frequencies can be affected by CRF, hearing impairment at high frequencies is most common [28]. In addition to antigenic similarity [29], the cochlea and kidney have similar physiological mechanisms, namely, the active transport of fluid and electrolytes achieved by the stria vascularis in the cochlea and

Several variables may contribute to the etiopathogenetic mechanisms of hearing

In an Iraqi study by Haider K et al. to determine the effect of hemodialysis on the hearing threshold in patients with chronic renal failure (CRF), 59 patients were followed up for 1 year with a pure-tone audiometric examination every 6 months [34]. At the beginning of the study, 39 patients (66.1%) had sensorineural hearing loss (SNHL). During the 12-month follow-up, 6 more patients developed SNHL giving a point prevalence rate of 76.3% at the end of the study. The hearing loss was more evident in the higher frequencies. Of the studied patients, 64.4% showed deterioration of the hearing threshold. The mean hearing threshold at the beginning of the study was 29.2 ± 21.1 dB versus 36.9 ± 17.3 dB at the end of the study (P < 0.001). No significant relation was found between age, sex, serum electrolytes, blood urea, and duration of CRF and hearing loss. Multivariate analysis showed that the duration of

It was previously confirmed that the cochlea is affected by the systemic metabolic, hydroelectrolytic, and hormonal alterations that are associated with

loss in CRF including factors related to the severity and duration of the disease, electrolyte disturbances, ototoxic drugs, age, comorbid conditions such as diabetes

hemodialysis was the only significant independent predictor of SNHL [34].

**3. Preventive healthcare strategies of sensorineural hearing loss**

Because of the global burden of patients receiving chronic hemodialysis therapy, coupled with the high prevalence of hearing loss among this cohort which are often overlooked [26, 27], it is proper to highlight on the need to create awareness on preventive measures of hearing loss. Also, worldwide, 120 million people are estimated to be suffering from disabling hearing loss (>40 dB, average 0.5–4 KHz) [35]. Primary preventive measures should include genetic counseling targeted at families known to carry diseased genes. In the prenatal period, efforts should be made to address maternal problems like premature deliveries, and low birth weight through

#### *Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

middle, and inner ear; and hearing loss [7, 17].

nels or upon disruption of barttin [22, 23].

**2.2 Medication toxic effect**

bilateral hypoplasia or dysplasia, unilateral renal agenesis with contralateral hypoplasia or dysplasia, ureteropelvic obstruction, and vesicoureteric reflux. Renal function ranges from normal to severe reduction in glomerular filtration rate [17]. The ear abnormalities range from preauricular pits, malformations in the external,

ClC-Kb/barttin (see **Figure 1**) is mainly expressed in basolateral membranes of the thick ascending limb of Henle's loop, where it is involved in the reabsorption of salt and, consequently, water [18]. In this part of the nephron, the Na + electrochemical gradient (created by basolateral Na+/K+ pump) drives the secondary active transport of NKCC2 (present in the apical membrane), accumulating Na+, Cl−, and K+ into the cell. K+ is extruded back to the lumen through ROMK K+ channels (also present in the apical membrane), whereas Na + and Cl − are reabsorbed by the interstitial fluid through the Na+/K+ pump and ClC-Kb channels, respectively. Thus, the end product of this system is the reabsorption of NaCl into the blood stream (**Figure 1A**). In the inner ear, both ClC-K isomers are expressed in the basolateral membrane of marginal cells of the stria vascularis. This multilayered epithelium is responsible for both the high concentration of K+ and the positive potential (about 100 mV higher than normal extracellular fluids) of the endolymph of the scala media, both of which are important properties for hearing. In marginal cells—the more apical layer in the stria vascularis—Na+/K+ pumps and NKCC1 transporters build up K+ and Cl − inside the cells. ClC-K/barttin channels recycle Cl − back to the interstitial fluid, while apical KCNQ1/KCNE1 K+ channels secrete the excess of potassium ions into the endolymph (**Figure 1B**) [19]. In agreement with the transport models involving ClCK/barttin channels, mutations in the gene encoding ClC-Kb cause salt-losing Bartter syndrome type III [20], characterized by hypokalemia, metabolic alkalosis and secondary hyperaldosteronism with normal or low blood pressure [21]. Mutations in the gene encoding barttin cause Bartter syndrome type IV that combines the salt wasting with congenital deafness, since both ClC-K proteins are non-functional in the absence of barttin [22]. When disruption occurs in only one of the ClC-K channels, as it does in ClCKb mutations in Bartter type III, hearing is preserved; the other isomer channel still provides the necessary Cl − recycling. Deafness occurs only on disruption of both ClC-K chan-

Over 450 medicines are reported to be ototoxic [24]. These include both prescription medicines such as antibiotics, cancer medications, anti-malarias, and diuretics; and over-the counter medicines such as Non-Steroidal Anti-Inflammatory drugs (Pain killers). In most cases, this type of ototoxicity is an acute, short-lived side effect; if the patient stops taking the medication, the symptoms typically recede [24]. This is not the case, however, for aminoglycoside antibiotics and platinum derivatives used as cancer drugs which may be associated with permanent

For the patient with CKD, the medications of importance in causing ototoxicity are the aminoglycoside antibiotics, used commonly in treating urinary tract infections and septicaemia which are quite frequent in such patients and also

hearing loss [25]. The mechanism of drug-induced ototoxicity is varied.

*2.2.1 Aminoglycoside antibiotics and high-ceiling diuretics*

*2.1.1.3 ClC-K in renal salt loss and deafness (Bartter syndrome type IV)*

**80**

furosemide; a high-ceiling diuretic commonly used in treating fluid overload and pulmonary oedema in CKD patients. Though the ototoxic effect of aminoglycoside is known among many medical practitioners, the lack of diagnostic facilities in many centers across the world lead to the neglect of full assessment for this potential side effect. Lack of treatment interventions for hearing loss in many regions take away the interest in evaluation for this side effect.

The ototoxicity of furosemide is often overlooked by physicians and nurses. Furosemide toxicity commonly occurs when the medicine is administered as intravenous push medication and in a faster fashion.

#### **2.3 Hearing loss among hemodialysis patients**

Chronic kidney disease patients in End stage who are on hemodialysis are another cohort of CKD patient who suffer from hearing loss.

Several reports indicate that sensorineural hearing loss (SNHL) is considerably more prevalent in patients with chronic renal failure (CRF) than in the general population. It ranges from 28% to 77% [26, 27].

Although all frequencies can be affected by CRF, hearing impairment at high frequencies is most common [28]. In addition to antigenic similarity [29], the cochlea and kidney have similar physiological mechanisms, namely, the active transport of fluid and electrolytes achieved by the stria vascularis in the cochlea and the glomeruli in the kidney [3].

It was previously confirmed that the cochlea is affected by the systemic metabolic, hydroelectrolytic, and hormonal alterations that are associated with CRF [30].

Several variables may contribute to the etiopathogenetic mechanisms of hearing loss in CRF including factors related to the severity and duration of the disease, electrolyte disturbances, ototoxic drugs, age, comorbid conditions such as diabetes mellitus and hypertension, and hemodialysis [31–33].

In an Iraqi study by Haider K et al. to determine the effect of hemodialysis on the hearing threshold in patients with chronic renal failure (CRF), 59 patients were followed up for 1 year with a pure-tone audiometric examination every 6 months [34]. At the beginning of the study, 39 patients (66.1%) had sensorineural hearing loss (SNHL). During the 12-month follow-up, 6 more patients developed SNHL giving a point prevalence rate of 76.3% at the end of the study. The hearing loss was more evident in the higher frequencies. Of the studied patients, 64.4% showed deterioration of the hearing threshold. The mean hearing threshold at the beginning of the study was 29.2 ± 21.1 dB versus 36.9 ± 17.3 dB at the end of the study (P < 0.001). No significant relation was found between age, sex, serum electrolytes, blood urea, and duration of CRF and hearing loss. Multivariate analysis showed that the duration of hemodialysis was the only significant independent predictor of SNHL [34].

#### **3. Preventive healthcare strategies of sensorineural hearing loss**

Because of the global burden of patients receiving chronic hemodialysis therapy, coupled with the high prevalence of hearing loss among this cohort which are often overlooked [26, 27], it is proper to highlight on the need to create awareness on preventive measures of hearing loss. Also, worldwide, 120 million people are estimated to be suffering from disabling hearing loss (>40 dB, average 0.5–4 KHz) [35]. Primary preventive measures should include genetic counseling targeted at families known to carry diseased genes. In the prenatal period, efforts should be made to address maternal problems like premature deliveries, and low birth weight through

improved antenatal care services. Perinatal/neonatal asphyxias, neonatal jaundices which requires exchange transfusions, neonatal meningitis etc. should be keenly addressed. There should be intensification of immunization programmes particularly those against meningitis, measles, mumps and rubella in selected populations.

There should be careful and judicious use of ototoxic drugs such as furosemide and aminoglycoside antibiotics in the clinical settings, avoiding combination of the two groups where possible. There should be education on the risk of self-medications, use of herbal products that may be both ototoxic and nephrotoxic.

Education on overcrowding in the daycare centers, poor housing systems, bottle feeding, malnutrition etc.

There should be better management of acute respiratory infections, noise control and the appropriate use of hearing protection. Education of individuals, communities and governments is an essential prerequisite to implementation [35].

Neonatal/early childhood hearing screening should be instituted for early identification, diagnosis, treatment and rehabilitation of high-risk patients.

There should be early identification and management of comorbidities like hypertension and diabetes in the adult population.

Among the dialysis population, awareness must be created and screening programmes instituted where possible.

Above all, rehabilitation programmes for affected individuals should be implemented to improve the quality of life of such individuals through the use of hearing aid and implants.

#### **4. Conclusions**

Hearing loss is not uncommonly associated with chronic kidney disease yet this co-morbidity is often overlooked by Health Care givers. The aetiopathogenesis of hearing loss in CKD patients are multifactorial; from genetic mutations that affect both the kidney and the inner ear due to similarities in structural proteins, through ototoxic medications commonly used in CKD patients, to the toxic effect of uraemia. It is hoped that this neglected aspect of care for patients with chronic kidney disease will receive the needed attention for holistic care of the CKD patient.

**83**

**Author details**

Sampson Antwi1

Technology, Kumasi, Ghana

Technology, Kumasi, Ghana

antwisampson.sms@knust.edu.gh

provided the original work is properly cited.

\* and Mohammed Duah Issahalq2

\*Address all correspondence to: kantwisampson@gmail.com;

1 Department of Child Health, Kwame Nkrumah University of Science and

2 Department of Otorhinolaryngology, Kwame Nkrumah University of science and

© 2021 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,

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

#### **Conflict of interest**

The authors declare no conflict of interest.

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

use of herbal products that may be both ototoxic and nephrotoxic.

hypertension and diabetes in the adult population.

The authors declare no conflict of interest.

programmes instituted where possible.

feeding, malnutrition etc.

aid and implants.

**4. Conclusions**

**Conflict of interest**

improved antenatal care services. Perinatal/neonatal asphyxias, neonatal jaundices which requires exchange transfusions, neonatal meningitis etc. should be keenly addressed. There should be intensification of immunization programmes particularly those against meningitis, measles, mumps and rubella in selected populations. There should be careful and judicious use of ototoxic drugs such as furosemide and aminoglycoside antibiotics in the clinical settings, avoiding combination of the two groups where possible. There should be education on the risk of self-medications,

Education on overcrowding in the daycare centers, poor housing systems, bottle

There should be better management of acute respiratory infections, noise control and the appropriate use of hearing protection. Education of individuals, communities and governments is an essential prerequisite to implementation [35]. Neonatal/early childhood hearing screening should be instituted for early identification, diagnosis, treatment and rehabilitation of high-risk patients. There should be early identification and management of comorbidities like

Among the dialysis population, awareness must be created and screening

Above all, rehabilitation programmes for affected individuals should be implemented to improve the quality of life of such individuals through the use of hearing

Hearing loss is not uncommonly associated with chronic kidney disease yet this co-morbidity is often overlooked by Health Care givers. The aetiopathogenesis of hearing loss in CKD patients are multifactorial; from genetic mutations that affect both the kidney and the inner ear due to similarities in structural proteins, through ototoxic medications commonly used in CKD patients, to the toxic effect of uraemia. It is hoped that this neglected aspect of care for patients with chronic kidney disease will receive the needed attention for holistic care of the CKD patient.

**82**

### **Author details**

Sampson Antwi1 \* and Mohammed Duah Issahalq2

1 Department of Child Health, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

2 Department of Otorhinolaryngology, Kwame Nkrumah University of science and Technology, Kumasi, Ghana

\*Address all correspondence to: kantwisampson@gmail.com; antwisampson.sms@knust.edu.gh

© 2021 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] Alford RL, Sutton VR (eds): Medical Genetics in the Clinical Practice of ORL. Advance Otorhinolaryngology. Basel, Karger, 2011, Vol 70, pp 75-83 (DOI:10.1159/00322478).

[2] El-Annor MW, El Sayed H, Khater A, Nada E. Audiological findings in children with Chronic Renal Failure on regular haemodialysis. Egypt J Otolaryngol [Serial online} 2013 cited 2020 Sept. 27; 29: 182-88. Available

[3] Ozturan O, Lam S. The effect of hemodialysis on hearing using pure-tone audiometry and distortionproduct otoacoustic emissions. ORL J Otorhinolaryngol Relat Spec 1998;60:306-313.

[4] Poroca DR, Pelis RM, Chappe VM. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies. Frontiers in Pharmacology, 2017; 8:151.

[5] Estévez R, Boettger T, Stein V, Birkenhäger R, Otto E, Hildebrandt F, et al. Barttin is a cl-channel β-subunit crucial for renal cl-reabsorption and inner ear K+ secretion. Nature, 2001; 414: 558-561. doi: 10.1038/35107099

[6] Birkenhager R, Otto E, Schurmann MJ. Mutations of BSND causes Barttersyndrome with sensorineuraldeafness and kidney failure. Nat Genet, 2001;29:310

[7] Seo1JY, Ko BS, Ha1 HT, Gong TH, Bong PJ, Dong-Joon Park DJ and Park YS.

[8] Meena RS, Aseri Y, Singh BK et al. Hearing loss in patients of chronic renal failure: a study of 100 cases. Indian J Otolaryngol Head Neck Surg; 64:356- 359; 2012

[9] Kovalik C.E. Endocrine and Neurologic manifestations of kidney failure. In: Greenberg A. Ed. Primer on Kidney Diseases. Pennsylvania: Saunders, 4th edition, 2005:pp527-536

[10] Jakic M, Mihaljevic D, Zibar L, Jakic M, Kotromanovic Z, Roguljic H. Sensorineural hearing loss in hemodialysis patients. Coll Antropol. 2010 Mar;34 Suppl 1:165-171.

[11] 2. Vilayur E, Gopinath B, Harris DC, Burlutsky G, McMahon CM, Mitchell P. The association between reduced GFR and hearing loss: a cross-sectional population-based study. Am J Kidney Dis. 2010 Oct;56(4):661-669.

[12] Ozturan O, Lam S. The effect of hemodialysis on hearing using pure-tone audiometry and distortionproduct otoacoustic emissions. ORL J Otorhinolaryngol Relat Spec. 1998 Nov;60(6):306-313.

[13] Adler D, Fiehn W, Ritz E. Inhibition of Na+,K+-stimulated ATPase in the cochlea of the guinea pig. A potential cause of disturbed inner ear function in terminal renal failure. Acta Otolaryngol. 1980;90(1-2):55-60.

[14] Albertazzi A, Cappelli P, Di MT, Maccarone M, Di PB. The natural history of uremic neuropathy. Contrib Nephrol. 1988;65:130-137.

[15] Gregory CM. Alport's syndrome and Related renal Disorders. In: Greenberg A (ed). Primer on Kidney Diseases. Philadelphia: Elsevier Saunders, 4th edition, 2005: PP363-367

[16] Cosgrove D, Samuelson G, Meehan DT, Miller C, McGee J, Walsh EJ, et al. Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome. Hear Res 1998 Jul;121(1-2):84-98.

**85**

NEJMoa032843

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

[17] Kaplan SB. Developmental

abnormalities of the Kidneys. In: Kaplan SB and Meyers ECK. Eds. Pediatric Nephrology and urology. Philadelphia: Elsevier Mosby, 2004: PP. 223-230

[24] https://www.soundrelief.com/ list-of-ototoxic-medications/.

[25] Lanvers-Kaminsky C, Zehnhoff-

Mechanisms, Pharmacogenetics, and protective strategies. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.603

[26] Meena RS, Aseri Y, Singh BK, Verma PC. Hearing loss in patients of chronic renal failure: A study of 100 cases. Indian J Otolaryngol Head Neck

[27] Bazzi C, Venturini CT, Pagani C, Arrigo G, D'Amico G. Hearing loss in short- and long-term haemodialysed patients. Nephrol Dial Transplant

[28] Jamaldeen J, Basheer A, Sarma AC, Kandasamy R. Prevalence and patterns

physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome.

of hearing loss among chronic kidney disease patients undergoing haemodialysis. Australas Med J

[29] Cosgrove D, Samuelson G, Meehan DT, Miller C, McGee J, Walsh EJ,et al. Ultrastructural,

Hear Res 1998;121:84-98.

[30] Pirodda A, Cicero AF,

2012;7(Suppl 2):S93–S95.

[32] Agarwal MK. A study of

otorhinolaryngological manifestations

Borghi C. Kidney disease and inner ear impairment: A simpler and closer pathogenic analogy? Intern Emerg Med

[31] Stavroulaki P, Nikolopoulos TP, Psarommatis I, Apostolopoulos N. Hearing evaluation with distortionproduct otoacoustic emissions in young patients undergoing haemodialysis. Clin Otolaryngol Allied Sci 2001;26:235-242.

Surg 2012;64:356-359.

1995;10:1865-1868.

2015;8:41-46.

Ciarimboli G. Drug-induced ototoxicity:

Dinnesen AG am, Parfitt R,

[18] Uchida, S., Sasaki, S., Nitta, K., Uchida, K., Horita, S., Nihei, H., et al. (1995). Localization and functional characterization of rat kidney- specific chloride channel,ClC-K1.J.Clin.Invest. 1995;95,104-113. doi:10.1172/JCI117626

[19] Rickheit, G., Maier, H., Strenzke, N., Andreescu, C. E., De, Zeeuw CI, Muenscher, A., et al. Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV. EMBO J.2008; 27,

2907-2917. doi:10.1038/emboj.

[20] Simon, D. B., Bindra, R. S., Mansfield, T. A., Nelson-Williams, C., Mendonca, E., and Stone, R. Mutations in the chloride channel gene, CLCNKB, cause bartter'ssyndrometypeIII.Nat. Genet. 1997; 17,171-178. doi:10.1038/

[21] Andrini, O., Keck, M., Briones, R., Lourdel, S., Vargas-Poussou, R., and Teulon, J. ClC-K chloride channels: emerging pathophysiology of bartter syndrome type 3. Am. J. Physiol. Renal Physiol. 2015; 308, F1324–F1334. doi:10.1152/ajprenal.00004.2015

[22] Brinkmeier H, and Jockusch H. Activators of protein kinase C induce myotonia by lowering chloride conductance in muscle. Biochem.

1987;148,1383-1389. doi:10.1016/

[23] Schlingmann, K. P., Konrad, M., Jeck, N., Waldegger, P., Reinalter, S. C., Holder, M., et al. Salt wasting and deafness resulting from mutations in two chloride channels. N. Engl. J. Med. 2004; 350, 1314-1319. doi: 10.1056/

Biophys. Res. Commun.

S0006-291X(87)80285-1

2008.203

ng1097-171

*Hearing Loss in Chronic Kidney Disease DOI: http://dx.doi.org/10.5772/intechopen.96572*

[17] Kaplan SB. Developmental abnormalities of the Kidneys. In: Kaplan SB and Meyers ECK. Eds. Pediatric Nephrology and urology. Philadelphia: Elsevier Mosby, 2004: PP. 223-230

[18] Uchida, S., Sasaki, S., Nitta, K., Uchida, K., Horita, S., Nihei, H., et al. (1995). Localization and functional characterization of rat kidney- specific chloride channel,ClC-K1.J.Clin.Invest. 1995;95,104-113. doi:10.1172/JCI117626

[19] Rickheit, G., Maier, H., Strenzke, N., Andreescu, C. E., De, Zeeuw CI, Muenscher, A., et al. Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV. EMBO J.2008; 27, 2907-2917. doi:10.1038/emboj. 2008.203

[20] Simon, D. B., Bindra, R. S., Mansfield, T. A., Nelson-Williams, C., Mendonca, E., and Stone, R. Mutations in the chloride channel gene, CLCNKB, cause bartter'ssyndrometypeIII.Nat. Genet. 1997; 17,171-178. doi:10.1038/ ng1097-171

[21] Andrini, O., Keck, M., Briones, R., Lourdel, S., Vargas-Poussou, R., and Teulon, J. ClC-K chloride channels: emerging pathophysiology of bartter syndrome type 3. Am. J. Physiol. Renal Physiol. 2015; 308, F1324–F1334. doi:10.1152/ajprenal.00004.2015

[22] Brinkmeier H, and Jockusch H. Activators of protein kinase C induce myotonia by lowering chloride conductance in muscle. Biochem. Biophys. Res. Commun. 1987;148,1383-1389. doi:10.1016/ S0006-291X(87)80285-1

[23] Schlingmann, K. P., Konrad, M., Jeck, N., Waldegger, P., Reinalter, S. C., Holder, M., et al. Salt wasting and deafness resulting from mutations in two chloride channels. N. Engl. J. Med. 2004; 350, 1314-1319. doi: 10.1056/ NEJMoa032843

[24] https://www.soundrelief.com/ list-of-ototoxic-medications/.

[25] Lanvers-Kaminsky C, Zehnhoff-Dinnesen AG am, Parfitt R, Ciarimboli G. Drug-induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies. Clinical Pharmacology and Therapeutics. https://doi.org/10.1002/cpt.603

[26] Meena RS, Aseri Y, Singh BK, Verma PC. Hearing loss in patients of chronic renal failure: A study of 100 cases. Indian J Otolaryngol Head Neck Surg 2012;64:356-359.

[27] Bazzi C, Venturini CT, Pagani C, Arrigo G, D'Amico G. Hearing loss in short- and long-term haemodialysed patients. Nephrol Dial Transplant 1995;10:1865-1868.

[28] Jamaldeen J, Basheer A, Sarma AC, Kandasamy R. Prevalence and patterns of hearing loss among chronic kidney disease patients undergoing haemodialysis. Australas Med J 2015;8:41-46.

[29] Cosgrove D, Samuelson G, Meehan DT, Miller C, McGee J, Walsh EJ,et al. Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome. Hear Res 1998;121:84-98.

[30] Pirodda A, Cicero AF, Borghi C. Kidney disease and inner ear impairment: A simpler and closer pathogenic analogy? Intern Emerg Med 2012;7(Suppl 2):S93–S95.

[31] Stavroulaki P, Nikolopoulos TP, Psarommatis I, Apostolopoulos N. Hearing evaluation with distortionproduct otoacoustic emissions in young patients undergoing haemodialysis. Clin Otolaryngol Allied Sci 2001;26:235-242.

[32] Agarwal MK. A study of otorhinolaryngological manifestations

**84**

Park YS.

359; 2012

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

[9] Kovalik C.E. Endocrine and Neurologic manifestations of kidney failure. In: Greenberg A. Ed. Primer on Kidney Diseases. Pennsylvania: Saunders, 4th edition, 2005:pp527-536

[10] Jakic M, Mihaljevic D, Zibar L,

Roguljic H. Sensorineural hearing loss in hemodialysis patients. Coll Antropol.

[11] 2. Vilayur E, Gopinath B, Harris DC, Burlutsky G, McMahon CM, Mitchell P. The association between reduced GFR and hearing loss: a cross-sectional population-based study. Am J Kidney

Jakic M, Kotromanovic Z,

2010 Mar;34 Suppl 1:165-171.

Dis. 2010 Oct;56(4):661-669.

Nov;60(6):306-313.

1980;90(1-2):55-60.

Nephrol. 1988;65:130-137.

edition, 2005: PP363-367

[16] Cosgrove D, Samuelson G, Meehan DT, Miller C, McGee J, Walsh EJ, et al. Ultrastructural,

[12] Ozturan O, Lam S. The effect of hemodialysis on hearing using pure-tone audiometry and distortionproduct otoacoustic emissions. ORL J Otorhinolaryngol Relat Spec. 1998

[13] Adler D, Fiehn W, Ritz E. Inhibition of Na+,K+-stimulated ATPase in the cochlea of the guinea pig. A potential cause of disturbed inner ear function in terminal renal failure. Acta Otolaryngol.

[14] Albertazzi A, Cappelli P, Di MT, Maccarone M, Di PB. The natural history of uremic neuropathy. Contrib

[15] Gregory CM. Alport's syndrome and Related renal Disorders. In: Greenberg A (ed). Primer on Kidney Diseases. Philadelphia: Elsevier Saunders, 4th

physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome. Hear Res 1998 Jul;121(1-2):84-98.

[1] Alford RL, Sutton VR (eds): Medical Genetics in the Clinical Practice of ORL. Advance Otorhinolaryngology. Basel, Karger, 2011, Vol 70, pp 75-83

(DOI:10.1159/00322478).

Available

**References**

1998;60:306-313.

10.1038/35107099

[6] Birkenhager R, Otto E,

Schurmann MJ. Mutations of BSND causes Barttersyndrome with sensorineuraldeafness and kidney failure. Nat Genet, 2001;29:310

[7] Seo1JY, Ko BS, Ha1 HT, Gong TH, Bong PJ, Dong-Joon Park DJ and

[8] Meena RS, Aseri Y, Singh BK et al. Hearing loss in patients of chronic renal failure: a study of 100 cases. Indian J Otolaryngol Head Neck Surg; 64:356-

[2] El-Annor MW, El Sayed H, Khater A, Nada E. Audiological findings in children with Chronic Renal Failure on regular haemodialysis. Egypt J Otolaryngol [Serial online} 2013 cited 2020 Sept. 27; 29: 182-88.

[3] Ozturan O, Lam S. The effect of hemodialysis on hearing using pure-tone audiometry and distortionproduct otoacoustic emissions. ORL J Otorhinolaryngol Relat Spec

[4] Poroca DR, Pelis RM, Chappe VM. ClC Channels and Transporters: Structure, Physiological Functions, and Implications in Human Chloride Channelopathies. Frontiers in Pharmacology, 2017; 8:151.

[5] Estévez R, Boettger T, Stein V, Birkenhäger R, Otto E, Hildebrandt F, et al. Barttin is a cl-channel β-subunit crucial for renal cl-reabsorption and inner ear K+ secretion. Nature, 2001; 414: 558-561. doi:

in patients of chronic renal failure. Indian J Otolaryngol Head Neck Surg 1997;49:316-320.

[33] Thodi C, Thodis E, Danielides V, Pasadakis P, Vargemezis V. Hearing in renal failure. Nephrol Dial Transplant 2006;21:3023-3030.

[34] Haider K. Saeed, Ahmed M. Al-Abbasia, Shukryia K. Al-Maliki, Jasim N. Al-Asadi. Sensorineural hearing loss in patients with chronic renal failure on hemodialysis in Basrah, Iraq. Tzu Chi Medical Journal 2018; 30(4): 216-220

[35] Alberti PW. The prevention of hearing loss worldwide. Scand Audiol Suppl. 1996; 42():15-19.

**87**

**Chapter 7**

**Abstract**

Mellitus

Brainstem Auditory Evoked

*Rajesh Paluru and Devendra Singh Negi*

sensitivity and 70–90% of specificity.

ture, and nutrient metabolism [2].

**1. Introduction**

impairment, inter peak latency, type 2 diabetes mellitus

Potentials in Type 2 Diabetes

Diabetes mellitus is a group of metabolic diseases characterized by

**Keywords:** Brainstem auditory evoked response, central neuropathy, hearing

Diabetes mellitus causes both peripheral and central neuropathy, but the peripheral diabetic neuropathy manifestations are more frequently discussed in the literature than the central diabetic neuropathy [1]. The central nervous system has wide, divergent afferent and efferent connections to integrate and transduced the whole body functions like homeostatic adjustments of food intake, energy expendi-

The auditory nervous system is a complex and intricate structure and performs many tasks in daily life; it analyzes, synthesizes, commands sensory information and carries out decisions; it is measured by using a powerful tool, auditory brainstem evoked response, is capable of both detection and diagnosis of brainstem lesions [3]. The auditory nervous system consists of ascending and descending pathways. Ascending pathway has the classical and non-classical pathways. The classical auditory pathways are known as the tonotopic system because they have

hyperglycaemia resulting from defects in insulin secretion, insulin action or both. Diabetes affects many systems and produces complications in the human body, in those complications one is diabetic central neuropathy. The pathological mechanisms involved in the central neuropathy include chronic hyperglycaemia, hypoglycaemic episodes, angiopathy and blood–brain barrier dysfunction. Diabetic central neuropathy is detected by using of brainstem auditory evoked response (BAER), Visual evoked potential (VEP), somatosensory evoked potential (SEP). These abnormalities are present at different levels and may appear before appearance of overt complications. The central nervous system abnormalities are more frequent in patients with peripheral neuropathy but evoked potentials can be abnormal even in patients without neuropathy. The BAER is a physiological recording technique to study the auditory pathway and does not require subject's attention and generates waves during the first 10 ms after the sound stimulus. Each BAER wave is generated by the activation of a sub-cortical component of the auditory pathway with 90%

#### **Chapter 7**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

in patients of chronic renal failure. Indian J Otolaryngol Head Neck Surg

[33] Thodi C, Thodis E, Danielides V, Pasadakis P, Vargemezis V. Hearing in renal failure. Nephrol Dial Transplant

[34] Haider K. Saeed, Ahmed M. Al-Abbasia, Shukryia K. Al-Maliki, Jasim N. Al-Asadi. Sensorineural hearing loss in patients with chronic renal failure on hemodialysis in Basrah, Iraq. Tzu Chi Medical Journal 2018;

[35] Alberti PW. The prevention of hearing loss worldwide. Scand Audiol

Suppl. 1996; 42():15-19.

1997;49:316-320.

2006;21:3023-3030.

30(4): 216-220

**86**

## Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus

*Rajesh Paluru and Devendra Singh Negi*

#### **Abstract**

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action or both. Diabetes affects many systems and produces complications in the human body, in those complications one is diabetic central neuropathy. The pathological mechanisms involved in the central neuropathy include chronic hyperglycaemia, hypoglycaemic episodes, angiopathy and blood–brain barrier dysfunction. Diabetic central neuropathy is detected by using of brainstem auditory evoked response (BAER), Visual evoked potential (VEP), somatosensory evoked potential (SEP). These abnormalities are present at different levels and may appear before appearance of overt complications. The central nervous system abnormalities are more frequent in patients with peripheral neuropathy but evoked potentials can be abnormal even in patients without neuropathy. The BAER is a physiological recording technique to study the auditory pathway and does not require subject's attention and generates waves during the first 10 ms after the sound stimulus. Each BAER wave is generated by the activation of a sub-cortical component of the auditory pathway with 90% sensitivity and 70–90% of specificity.

**Keywords:** Brainstem auditory evoked response, central neuropathy, hearing impairment, inter peak latency, type 2 diabetes mellitus

#### **1. Introduction**

Diabetes mellitus causes both peripheral and central neuropathy, but the peripheral diabetic neuropathy manifestations are more frequently discussed in the literature than the central diabetic neuropathy [1]. The central nervous system has wide, divergent afferent and efferent connections to integrate and transduced the whole body functions like homeostatic adjustments of food intake, energy expenditure, and nutrient metabolism [2].

The auditory nervous system is a complex and intricate structure and performs many tasks in daily life; it analyzes, synthesizes, commands sensory information and carries out decisions; it is measured by using a powerful tool, auditory brainstem evoked response, is capable of both detection and diagnosis of brainstem lesions [3]. The auditory nervous system consists of ascending and descending pathways. Ascending pathway has the classical and non-classical pathways. The classical auditory pathways are known as the tonotopic system because they have

distinct frequency tuning and the neurons are organized anatomically according to the frequency to which they are tuned. Non-classical pathway used the dorsal nuclei of the thalamus and that project to secondary auditory cortex rather than primary auditory cortex. Again the non-classical pathway divided into two separate systems, the diffuse and the polysensory pathways. Descending pathway has the corticofugal and the olivocochlear pathways. Descending auditory pathways are organized mostly parallel to the ascending pathways extending from the cerebral cortex to the cochlear hair cells [4].

Evoked potentials are helpful very much to study the diabetic change in central neural structures [5]. Diabetic central neuropathy is detected by using of brainstem auditory evoked response (BAER), Visual evoked potential (VEP), somatosensory evoked potential (SEP) [5, 6]. These abnormalities are present at different levels and may appear before appearance of overt complications. The central nervous system abnormalities are more frequent in patients with peripheral neuropathy but evoked potentials can be abnormal even in patients without neuropathy. The pathological mechanisms involved in the central neuropathy include chronic hyperglycaemia, hypoglycaemic episodes, angiopathy and blood–brain barrier dysfunction [7].

The BAER is a physiological recording technique to study the auditory pathway and does not require subject's attention and generates waves during the first 10 ms after the sound stimulus. Each ABR wave is generated by the activation of a subcortical component of the auditory pathway [8] with 90% sensitivity and 70–90% of specificity [9]. Despite its fall from favor as the initial test of choice in suspected brainstem or VIIIth cranial nerve disease, important clinical roles for BAER still exist. It should be remembered that BAER assess functions of auditory pathways whereas neuroimaging studies examine structure [10].

#### **2. Materials and methods**

#### **2.1 Research design**

The research design is cross sectional study. The control group included normal subjects, T2DM patients without hearing impairment of either sex, who is not suffering from hearing problems. The sampling technique was sequential sampling.

#### **2.2 Participants**

The present study was carried out at Mediciti Institute of Medical Sciences (MIMS), Hyderabad, India during the period of 2015 to 2016. This study was approved by institutional ethical committee (FWA00002084; dated 16/03/2015). In this study three groups i.e. WoHI (n = 50), WHI (n = 50) and normal subjects (n = 10) of either sex with an age group of 35–55 were included. The participants were enrolled in the study after acquiring the informed consent.

#### **2.3 Inclusion and exclusion criteria**

Type 2 diabetic patients with (WHI) and without (WoHI) hearing impairment, both the gender was included with age limit between 35 and 55 years; minimum duration of diabetes after the diagnosis was 5 years and also ten normal subjects were included as controls.

Participants who had a history of immune/metabolic diseases like hyperbilirubinaemia/kernicterus, polyarteritis nodosa, type 1 diabetes, paraproteinaemias,

**89**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

anoxia/hypoxia, sarcoidosis, rheumatoid arthritis, uraemia, Guillain-Barré Syndrome, chronic infections like Leprosy, AIDS, Borreliosis, Ramsey Hunt syndrome, using heavy metals like lead, cobalt, mercury; drugs like carboplatin, methyldopa and reserpine; neoplasma/intracranial cystic lesions, chronic middle ear diseases, cranial trauma, ear surgeries, recent surgeries, congenital problems, noise exposure, smoking, alcoholism, hypertension, stroke and hepatic encepha-

The sample size was calculated in the OpenEpi statistical software. In the pilot study, screening for hearing was carried out for both the ears in fifteen individuals by using pure tone audiometry. In the right ear, 9 out of 15 had a hearing impairment, and 5 out of 9 (55.5%) participants with hearing impairment had diabetes. Out of the 6 (16.7%) individuals without hearing impairment only one had diabetes. Using these values sample size was calculated as 27 each for controls and test. In the left ear, 10 out of 15 had a hearing impairment, and 5 out of 10 (50%) subjects with hearing impairment had diabetes. Out of the 5 (20%) individuals without hearing impairment only one had diabetes. Using these values sample size was calculated as 45 each for controls and test. So in the present study 50 was considered

Height and weight were measured on the subjects in standing position. The weighing scales and the measuring tapes were calibrated periodically. BMI was cal-

below 18.5 (underweight), 18.5–24.9 (normal), 25.0–29.9 (pre obesity), 30.0–34.9 (obesity class I), 35.0–39.9 (Obesity class II) and Above 40 (Obesity class III).

In diabetes, long-term maintenance of blood glucose is important to prevent complications. HbA1cis an indicator of the average glucose concentration in the blood over a period of four months. The HbA1c was measured by using anticaogulated venous blood with latex agglutination inhibition assay (the absence of agglutination is diagnostic of antigen provides a high sensitive assay for small quantities of antigen) with "Rx imola automated analyser (open system)". Protease enzyme in the hemoglobin denaturant reagent lyses red blood cells and causes hydrolysis of the hemoglobin. The concentration of HbA1c and the total hemoglobin concentrations are measured and HbA1c was calculated as a % of the total hemoglobin concentration. A normal range of HbA1c was 4–6.5% (normal), 6.5–7.5% (target range for

those with diabetes), 8–9.5% (high) and greater than 9.5% (very high).

The levels of hearing impairment are assessed with the help of Pure Tone Audiometry and obtain pure tone thresholds during air and bone conduction testing. They are recorded graphically on the "audiogram". The audiogram is graph of a patient's hearing thresholds across the frequency octaves from 250 Hz to 8000 Hz. The audiogram provides both qualitative and quantitative information about the patient's hearing loss. Quantitative information tells about degree of loss based on the pure tone average (PTA) of AC thresholds and calculated as decibels (dB). PTA

**2.7 Measurement of pure tone average (PTA)**

(mts). BMI normal values are

culated from the formula, BMI = weight (kg) /height2

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

lopathy were excluded from the study.

**2.4 Sample size calculation**

as sample size for each group.

**2.6 Measurement of HbA1c**

**2.5 Calculation of BMI**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

anoxia/hypoxia, sarcoidosis, rheumatoid arthritis, uraemia, Guillain-Barré Syndrome, chronic infections like Leprosy, AIDS, Borreliosis, Ramsey Hunt syndrome, using heavy metals like lead, cobalt, mercury; drugs like carboplatin, methyldopa and reserpine; neoplasma/intracranial cystic lesions, chronic middle ear diseases, cranial trauma, ear surgeries, recent surgeries, congenital problems, noise exposure, smoking, alcoholism, hypertension, stroke and hepatic encephalopathy were excluded from the study.

#### **2.4 Sample size calculation**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

whereas neuroimaging studies examine structure [10].

cochlear hair cells [4].

dysfunction [7].

**2. Materials and methods**

**2.3 Inclusion and exclusion criteria**

were included as controls.

**2.1 Research design**

**2.2 Participants**

distinct frequency tuning and the neurons are organized anatomically according to the frequency to which they are tuned. Non-classical pathway used the dorsal nuclei of the thalamus and that project to secondary auditory cortex rather than primary auditory cortex. Again the non-classical pathway divided into two separate systems, the diffuse and the polysensory pathways. Descending pathway has the corticofugal and the olivocochlear pathways. Descending auditory pathways are organized mostly parallel to the ascending pathways extending from the cerebral cortex to the

Evoked potentials are helpful very much to study the diabetic change in central neural structures [5]. Diabetic central neuropathy is detected by using of brainstem auditory evoked response (BAER), Visual evoked potential (VEP), somatosensory evoked potential (SEP) [5, 6]. These abnormalities are present at different levels and may appear before appearance of overt complications. The central nervous system abnormalities are more frequent in patients with peripheral neuropathy but evoked potentials can be abnormal even in patients without neuropathy. The pathological mechanisms involved in the central neuropathy include chronic hyperglycaemia, hypoglycaemic episodes, angiopathy and blood–brain barrier

The BAER is a physiological recording technique to study the auditory pathway and does not require subject's attention and generates waves during the first 10 ms after the sound stimulus. Each ABR wave is generated by the activation of a subcortical component of the auditory pathway [8] with 90% sensitivity and 70–90% of specificity [9]. Despite its fall from favor as the initial test of choice in suspected brainstem or VIIIth cranial nerve disease, important clinical roles for BAER still exist. It should be remembered that BAER assess functions of auditory pathways

The research design is cross sectional study. The control group included normal subjects, T2DM patients without hearing impairment of either sex, who is not suffering from hearing problems. The sampling technique was sequential sampling.

The present study was carried out at Mediciti Institute of Medical Sciences (MIMS), Hyderabad, India during the period of 2015 to 2016. This study was approved by institutional ethical committee (FWA00002084; dated 16/03/2015). In this study three groups i.e. WoHI (n = 50), WHI (n = 50) and normal subjects (n = 10) of either sex with an age group of 35–55 were included. The participants

Type 2 diabetic patients with (WHI) and without (WoHI) hearing impairment, both the gender was included with age limit between 35 and 55 years; minimum duration of diabetes after the diagnosis was 5 years and also ten normal subjects

Participants who had a history of immune/metabolic diseases like hyperbilirubinaemia/kernicterus, polyarteritis nodosa, type 1 diabetes, paraproteinaemias,

were enrolled in the study after acquiring the informed consent.

**88**

The sample size was calculated in the OpenEpi statistical software. In the pilot study, screening for hearing was carried out for both the ears in fifteen individuals by using pure tone audiometry. In the right ear, 9 out of 15 had a hearing impairment, and 5 out of 9 (55.5%) participants with hearing impairment had diabetes. Out of the 6 (16.7%) individuals without hearing impairment only one had diabetes. Using these values sample size was calculated as 27 each for controls and test. In the left ear, 10 out of 15 had a hearing impairment, and 5 out of 10 (50%) subjects with hearing impairment had diabetes. Out of the 5 (20%) individuals without hearing impairment only one had diabetes. Using these values sample size was calculated as 45 each for controls and test. So in the present study 50 was considered as sample size for each group.

#### **2.5 Calculation of BMI**

Height and weight were measured on the subjects in standing position. The weighing scales and the measuring tapes were calibrated periodically. BMI was calculated from the formula, BMI = weight (kg) /height2 (mts). BMI normal values are below 18.5 (underweight), 18.5–24.9 (normal), 25.0–29.9 (pre obesity), 30.0–34.9 (obesity class I), 35.0–39.9 (Obesity class II) and Above 40 (Obesity class III).

#### **2.6 Measurement of HbA1c**

In diabetes, long-term maintenance of blood glucose is important to prevent complications. HbA1cis an indicator of the average glucose concentration in the blood over a period of four months. The HbA1c was measured by using anticaogulated venous blood with latex agglutination inhibition assay (the absence of agglutination is diagnostic of antigen provides a high sensitive assay for small quantities of antigen) with "Rx imola automated analyser (open system)". Protease enzyme in the hemoglobin denaturant reagent lyses red blood cells and causes hydrolysis of the hemoglobin. The concentration of HbA1c and the total hemoglobin concentrations are measured and HbA1c was calculated as a % of the total hemoglobin concentration. A normal range of HbA1c was 4–6.5% (normal), 6.5–7.5% (target range for those with diabetes), 8–9.5% (high) and greater than 9.5% (very high).

#### **2.7 Measurement of pure tone average (PTA)**

The levels of hearing impairment are assessed with the help of Pure Tone Audiometry and obtain pure tone thresholds during air and bone conduction testing. They are recorded graphically on the "audiogram". The audiogram is graph of a patient's hearing thresholds across the frequency octaves from 250 Hz to 8000 Hz. The audiogram provides both qualitative and quantitative information about the patient's hearing loss. Quantitative information tells about degree of loss based on the pure tone average (PTA) of AC thresholds and calculated as decibels (dB). PTA

normal ranges for hearing impairment are −10 to 15 (normal), 16 to 25 (slight), 26 to 40 (mild), 41 to 55 (moderate), 56 to 70 (moderately severe), 71 to 90 (severe), 91 and above (profound). Qualitative information tells about type of hearing impairment and helps in topological diagnosis.

#### **2.8 Recording of brainstem auditory evoked response**

The BAER is a sequential electrical potential generated in the brainstem and auditory pathway in response to stimulus and is recorded as wave forms from wave I to wave VII and these peaks are generated from different sites of the brainstem auditory pathway. It helps in analyzing presence or absence of hearing loss at the level of central auditory pathway. In the present BAER is recorded by using instrument "Biologic Navigator Pro system AEP Software version 6.3" Natus Medical Incorporated USA, 2013.

#### *2.8.1 Stimulus types*

An ideal stimulus for eliciting BEAR is a click, which is a brief rectangular pulse of 50–200 μs duration with an instantaneous onset. The rapid onset of click provides good neural synchrony, thereby eliciting a clearly defined BAER.

#### *2.8.2 Electrode application*

Skin must be thoroughly cleaned to remove excess oil, dead skin and dirt to obtain a good contact between skin and electrode. Electrodes are filled with a conducting cream and taped into place. Once the electrodes have been applied, adequacy of contact with skin is assessed by measuring electrical impedance between each electrode pair. For high quality recording, inter electrode impedance ≤5 kΩ is acceptable.

#### *2.8.3 Processing of electrical activity*

Electrical activity picked up by the recording electrodes within the specified time window must be processed through several stages to visualize the BAER waveform. This is because the BAER peaks are of extremely small voltage (>1 μV) and are buried in a background of interference (termed 'noise'), which includes ongoing electroencephalogram (EEG) activity, muscle potentials caused by movement or tension, and 50 Hz power-line radiation. The stages of processing include amplification, filtering, and signal averaging.

#### *2.8.4 Amplification and filtering*

The small size of the BAER peaks requires amplification to increase the magnitude of the electrical activity picked up by the electrodes. An amplifier gain of 105 is typically used. The problem of interference obscuring the BAER can be diminished partially by filtering the electrical activity coming from the electrodes. Band pass filters are used to accept energy only within the particular frequency band of interest and reject energy in other frequency ranges. For BAER recording, a filter setting of 30–3000 Hz is recommended to enhance the BAER when testing infants.

Filtering can only eliminate a portion of the interfering noise because of overlap between the frequency content of the BAER and the frequency of the interference. Therefore, another technique, called signal averaging, must be used to further reduce unwanted interference.

**91**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

The BAER is very small, and even with filtering, it is buried with a background of noise. Signal averaging helps to reduce this noise so that the signal, in this case the BAER, can be detected. Signal averaging is possible because the BAER is timelocked to stimulus onset, whereas the noise interference occurs randomly. That is, the signal occurs at the same points in time following onset of the eliciting stimulus, but the noise has no regular pattern. In signal averaging, a large number of stimuli are presented, and the responses to each of the individual stimulus presentations (termed 'sweeps') are averaged together to obtain a final averaged waveform. By averaging, the random noise tends to cancel out, whereas the evoked potential is retained because it is basically the same in each sweep. The greater the number of stimulus presentations used, the greater the improvement in signal to noise ratio, and the more clearly the BAER can be visualized in the final averaged waveform.

The patient is made to lie down in a relaxed position with eyes closed so that no auro-palpaberal reflex could be picked up. The portion behind the ear i.e., mastoid on both sides and the forehead are rubbed gently with a conductive gel such that it allows to maintain adequate impedance for the testing. Measures are taken that there no particulars in the testing area that could cause electrical artifacts. Care should also be taken that the wires embedded to the instrument are un-tangled. Considering the test particulars, click stimulus with an alternating polarity are used at intensity levels 80, 70, 60, 50, 40, 30 dB NHL. The filter setting that is set ranges from 150 Hz–1500 Hz, with an epoch time of 10.26 ms and stimulus rate of 11.1/sec and 1024 sweeps of stimulus. The waveform thus displayed post averaging process on the screen is analyzed and the peaks I, III and V are noted. The results thus obtained are analyzed for the final diagnosis considering the absolute latencies of peaks I, III and V and inter peak latencies of I-III, III-V and III-V respectively. Waves I-VII are originated from cochlear nerve, cochlear nucleus, superior olivary complex, lateral lemniscus,

inferior colliculus, medial geniculate body and auditory cortex respectively.

IPL I-III is the conduction from the eighth nerve across the subarachnoid space,

All the data were expressed as mean ± SE. The mean were analyzed by one way ANOVA (Student–Newman–Keuls method). Pearson correlation test was done to see the relationship between right and left ear inter peak latencies of wave I-III, III-V and I-V values in normal subjects, WoHI and WHI groups. Pearson correlation test was done to see the relationship between inter peak latencies I-III, III-V and I-V with age, BMI and HbA1c values in normal subjects, WoHI and WHI groups for both the ears. For all the statistics and graph plotting, SigmaPlot 13.0 (Systat software, USA)

into the core of the lower pons; normal is 2 milli secs and abnormal is ˃2.4 milli secs. IPL III-V is the conduction from the lower to the upper pons and possibly into the midbrain; normal is 2 milli secs and abnormal is ˃2.4 milli secs. IPL I-V is the conduction from the proximal eighth nerve through pons and into the midbrain;

normal 4 milli secs and abnormal is ˃4.4 milli secs.

was used. P < 0.05 was considered as significant.

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

*2.8.5 Signal averaging*

*2.8.6 Procedure*

*2.8.7 Interpretation*

**3. Statistical analysis**

#### *2.8.5 Signal averaging*

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

**2.8 Recording of brainstem auditory evoked response**

impairment and helps in topological diagnosis.

Incorporated USA, 2013.

*2.8.2 Electrode application*

≤5 kΩ is acceptable.

*2.8.3 Processing of electrical activity*

*2.8.4 Amplification and filtering*

reduce unwanted interference.

amplification, filtering, and signal averaging.

*2.8.1 Stimulus types*

normal ranges for hearing impairment are −10 to 15 (normal), 16 to 25 (slight), 26 to 40 (mild), 41 to 55 (moderate), 56 to 70 (moderately severe), 71 to 90 (severe), 91 and above (profound). Qualitative information tells about type of hearing

The BAER is a sequential electrical potential generated in the brainstem and auditory pathway in response to stimulus and is recorded as wave forms from wave I to wave VII and these peaks are generated from different sites of the brainstem auditory pathway. It helps in analyzing presence or absence of hearing loss at the level of central auditory pathway. In the present BAER is recorded by using instrument "Biologic Navigator Pro system AEP Software version 6.3" Natus Medical

An ideal stimulus for eliciting BEAR is a click, which is a brief rectangular pulse of 50–200 μs duration with an instantaneous onset. The rapid onset of click pro-

Skin must be thoroughly cleaned to remove excess oil, dead skin and dirt to obtain a good contact between skin and electrode. Electrodes are filled with a conducting cream and taped into place. Once the electrodes have been applied, adequacy of contact with skin is assessed by measuring electrical impedance between each electrode pair. For high quality recording, inter electrode impedance

Electrical activity picked up by the recording electrodes within the specified time window must be processed through several stages to visualize the BAER waveform. This is because the BAER peaks are of extremely small voltage (>1 μV) and are buried in a background of interference (termed 'noise'), which includes ongoing electroencephalogram (EEG) activity, muscle potentials caused by movement or tension, and 50 Hz power-line radiation. The stages of processing include

The small size of the BAER peaks requires amplification to increase the magnitude of the electrical activity picked up by the electrodes. An amplifier gain of 105

typically used. The problem of interference obscuring the BAER can be diminished partially by filtering the electrical activity coming from the electrodes. Band pass filters are used to accept energy only within the particular frequency band of interest and reject energy in other frequency ranges. For BAER recording, a filter setting

Filtering can only eliminate a portion of the interfering noise because of overlap between the frequency content of the BAER and the frequency of the interference. Therefore, another technique, called signal averaging, must be used to further

of 30–3000 Hz is recommended to enhance the BAER when testing infants.

is

vides good neural synchrony, thereby eliciting a clearly defined BAER.

**90**

The BAER is very small, and even with filtering, it is buried with a background of noise. Signal averaging helps to reduce this noise so that the signal, in this case the BAER, can be detected. Signal averaging is possible because the BAER is timelocked to stimulus onset, whereas the noise interference occurs randomly. That is, the signal occurs at the same points in time following onset of the eliciting stimulus, but the noise has no regular pattern. In signal averaging, a large number of stimuli are presented, and the responses to each of the individual stimulus presentations (termed 'sweeps') are averaged together to obtain a final averaged waveform. By averaging, the random noise tends to cancel out, whereas the evoked potential is retained because it is basically the same in each sweep. The greater the number of stimulus presentations used, the greater the improvement in signal to noise ratio, and the more clearly the BAER can be visualized in the final averaged waveform.

#### *2.8.6 Procedure*

The patient is made to lie down in a relaxed position with eyes closed so that no auro-palpaberal reflex could be picked up. The portion behind the ear i.e., mastoid on both sides and the forehead are rubbed gently with a conductive gel such that it allows to maintain adequate impedance for the testing. Measures are taken that there no particulars in the testing area that could cause electrical artifacts. Care should also be taken that the wires embedded to the instrument are un-tangled. Considering the test particulars, click stimulus with an alternating polarity are used at intensity levels 80, 70, 60, 50, 40, 30 dB NHL. The filter setting that is set ranges from 150 Hz–1500 Hz, with an epoch time of 10.26 ms and stimulus rate of 11.1/sec and 1024 sweeps of stimulus. The waveform thus displayed post averaging process on the screen is analyzed and the peaks I, III and V are noted. The results thus obtained are analyzed for the final diagnosis considering the absolute latencies of peaks I, III and V and inter peak latencies of I-III, III-V and III-V respectively. Waves I-VII are originated from cochlear nerve, cochlear nucleus, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body and auditory cortex respectively.

#### *2.8.7 Interpretation*

IPL I-III is the conduction from the eighth nerve across the subarachnoid space, into the core of the lower pons; normal is 2 milli secs and abnormal is ˃2.4 milli secs. IPL III-V is the conduction from the lower to the upper pons and possibly into the midbrain; normal is 2 milli secs and abnormal is ˃2.4 milli secs. IPL I-V is the conduction from the proximal eighth nerve through pons and into the midbrain; normal 4 milli secs and abnormal is ˃4.4 milli secs.

#### **3. Statistical analysis**

All the data were expressed as mean ± SE. The mean were analyzed by one way ANOVA (Student–Newman–Keuls method). Pearson correlation test was done to see the relationship between right and left ear inter peak latencies of wave I-III, III-V and I-V values in normal subjects, WoHI and WHI groups. Pearson correlation test was done to see the relationship between inter peak latencies I-III, III-V and I-V with age, BMI and HbA1c values in normal subjects, WoHI and WHI groups for both the ears. For all the statistics and graph plotting, SigmaPlot 13.0 (Systat software, USA) was used. P < 0.05 was considered as significant.

#### **4. Results**

The comparison of IPLs I-III, III-V and I-V of both the ears in normal subjects, WoHI and WHI groups were done by one way analysis of variance and it was represented in **Table 1** with their mean and standard error of mean. The comparison of IPL I-III of BAER of both the ears in normal subjects, WoHI and WHI groups were given in **Figure 1**. The IPL I-III of both the ears in WHI group was statistically different from normal subjects and WoHI groups (P < 0.0001), this showed that IPL I-III increased in both ears of WHI group. The correlation of IPL I-III values of both the ears in WoHI and WHI groups were given in **Figure 2**. Negative correlation is seen in WoHI group for both the ears (P = 0.730), whereas in WHI group it is statistically significant (P = 0.050).

The comparison of IPL III-V of BAER of both the ears in normal subjects, WoHI and WHI groups were given in **Figure 3**. The right ear IPL III-V of WHI group


#### **Table 1.**

*One way analysis of variance of IPLs in normal subjects, T2DM WoHI and WHI groups.*

#### **Figure 1.**

*The IPL I-III in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal subjects; b – Significantly different from WoHI group.*

**93**

**Figure 3.**

*subjects; b – Significantly different from WoHI group.*

**Figure 2.**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

*Correlation of IPL I-III (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*The IPL III-V in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal* 

*n = 50 each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

#### **Figure 2.**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

statistically significant (P = 0.050).

**Parameter Ear Normal subjects** 

The comparison of IPLs I-III, III-V and I-V of both the ears in normal subjects,

The comparison of IPL III-V of BAER of both the ears in normal subjects, WoHI

IPL I-III (ms) Right 1.688 ± 0.059 1.895 ± 0.048 2.241 ± 0.039 Given in

Left 1.521 ± 0.051 1.818 ± 0.053 1.662 ± 0.038

Left 2.919 ± 0.174 3.845 ± 0.052 3.715 ± 0.043

**T2DM WoHI (Mean ± SEM)**

**Figure 1** Left 1.695 ± 0.056 2.027 ± 0.317 2.187 ± 0.048

**T2DM WHI (Mean ± SEM)** **P-value**

and WHI groups were given in **Figure 3**. The right ear IPL III-V of WHI group

**(Mean ± SEM)**

IPL III-V (ms) Right 1.596 ± 0.044 1.896 ± 0.048 1.930 ± 0.053

IPL I-V (ms) Right 3.081 ± 0.201 4.083 ± 0.050 4.170 ± 0.058

*One way analysis of variance of IPLs in normal subjects, T2DM WoHI and WHI groups.*

WoHI and WHI groups were done by one way analysis of variance and it was represented in **Table 1** with their mean and standard error of mean. The comparison of IPL I-III of BAER of both the ears in normal subjects, WoHI and WHI groups were given in **Figure 1**. The IPL I-III of both the ears in WHI group was statistically different from normal subjects and WoHI groups (P < 0.0001), this showed that IPL I-III increased in both ears of WHI group. The correlation of IPL I-III values of both the ears in WoHI and WHI groups were given in **Figure 2**. Negative correlation is seen in WoHI group for both the ears (P = 0.730), whereas in WHI group it is

**4. Results**

**92**

**Figure 1.**

**Table 1.**

*subjects; b – Significantly different from WoHI group.*

*The IPL I-III in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal* 

*Correlation of IPL I-III (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. n = 50 each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 3.**

*The IPL III-V in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal subjects; b – Significantly different from WoHI group.*

(P = 0.022) were statistically different from normal subjects, WoHI group. The left ear IPL III-V of WoHI group is significantly different from normal subjects whereas WHI group is significantly different from WoHI group. This showed that IPL III-V increased in both ears of WHI group. The correlation of IPL III-V values of both the ears in WoHI and WHI groups were given in **Figure 4**. No correlation is seen in WoHI and WHI groups for both the ears. Negative correlation is seen WoHI group for both the ears (P = 0.100).

The comparison of IPL I-V of BAER of both the ears in normal subjects, WoHI and WHI groups were given in **Figure 5**. In WoHI and WHI groups (P < 0.0001), both the ears showed significant difference from the normal subjects. The correlation of IPL I-V values of both the ears in WoHI and WHI groups were given in **Figure 6**. No correlation was seen in WoHI and WHI groups for both the ears.

The correlation of IPL values and age, BMI, HbA1c values for both the ears in normal subjects were given in **Table 2**. The age, BMI, HbA1c values are not correlated with IPL values in normal subjects. The correlation of IPL values and age, BMI, HbA1c values for both the ears in all subjects were given in **Table 3**. The BMI correlated with the IPL I-V (P = 0.003) of both the ears and HbA1c values correlated with IPL I-III (P = 0.003), I-V (P < 0.001) values of both ears in all subjects. This showed that with increase in BMI and HbA1c values, the IPL values are increased in diabetic subjects.

The correlation of IPL I-III, III-V and I-V values and age for both the ears in WoHI and WHI groups were given in **Figures 7**–**9**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with age. In the IPL I-III, left ear (P = 0.262) of WoHI and right ear (P = 0.735) of WHI groups shows negative correlation with age. In the IPL III-V, right ear (P = 0.460) of WoHI group shows negative correlation with age. In the IPL I-V, right (P = 0.757) and left (P = 0.433) ears of WoHI group and left (P = 0.826) ear of WHI group shows negative correlation with age.

#### **Figure 4.**

*Correlation of IPL III-V (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. n = 50 each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

**95**

**Figure 6.**

**Figure 5.**

The correlation of IPL I-III, III-V and I-V values and BMI for both the ears in WoHI and WHI groups were given in **Figures 10–12**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with BMI. In IPL I-III,

*Correlation of IPL I-V (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. n = 50* 

*each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

*The IPL I-V in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal* 

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

*subjects; b – Significantly different from WoHI group.*

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

**Figure 5.**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

for both the ears (P = 0.100).

(P = 0.022) were statistically different from normal subjects, WoHI group. The left ear IPL III-V of WoHI group is significantly different from normal subjects whereas WHI group is significantly different from WoHI group. This showed that IPL III-V increased in both ears of WHI group. The correlation of IPL III-V values of both the ears in WoHI and WHI groups were given in **Figure 4**. No correlation is seen in WoHI and WHI groups for both the ears. Negative correlation is seen WoHI group

The comparison of IPL I-V of BAER of both the ears in normal subjects, WoHI and WHI groups were given in **Figure 5**. In WoHI and WHI groups (P < 0.0001), both the ears showed significant difference from the normal subjects. The correlation of IPL I-V values of both the ears in WoHI and WHI groups were given in **Figure 6**. No correlation was seen in WoHI and WHI groups for both the ears. The correlation of IPL values and age, BMI, HbA1c values for both the ears in normal subjects were given in **Table 2**. The age, BMI, HbA1c values are not correlated with IPL values in normal subjects. The correlation of IPL values and age, BMI, HbA1c values for both the ears in all subjects were given in **Table 3**. The BMI correlated with the IPL I-V (P = 0.003) of both the ears and HbA1c values correlated with IPL I-III (P = 0.003), I-V (P < 0.001) values of both ears in all subjects. This showed that with increase in BMI and HbA1c values, the IPL values are increased in diabetic subjects. The correlation of IPL I-III, III-V and I-V values and age for both the ears in WoHI and WHI groups were given in **Figures 7**–**9**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with age. In the IPL I-III, left ear (P = 0.262) of WoHI and right ear (P = 0.735) of WHI groups shows negative correlation with age. In the IPL III-V, right ear (P = 0.460) of WoHI group shows negative correlation with age. In the IPL I-V, right (P = 0.757) and left (P = 0.433) ears of WoHI group and

left (P = 0.826) ear of WHI group shows negative correlation with age.

*Correlation of IPL III-V (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*n = 50 each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

**94**

**Figure 4.**

*The IPL I-V in normal subjects, type 2 diabetes without (WoHI) and with (WHI) hearing impairment. Mean + SE (n ± 50 each in WoHI and WHI groups, n ± 10 in normal subjects). The 'F' and P values are comparing normal subjects, WoHI and WHI of right and left ear. a – Significantly different from normal subjects; b – Significantly different from WoHI group.*

#### **Figure 6.**

*Correlation of IPL I-V (ms) in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. n = 50 each. The 'r' and P values are correlating WoHI and WHI right and left ear.*

The correlation of IPL I-III, III-V and I-V values and BMI for both the ears in WoHI and WHI groups were given in **Figures 10–12**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with BMI. In IPL I-III,



#### **Table 2.**

*Correlation of independent variables and IPLs in normal subjects.*


**97**

**Figure 8.**

**Figure 7.**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

*Correlation of IPL I-III and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*Correlation of IPL III-V and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

**Table 3.** *Correlation of independent variables and IPLs in all subjects.* *Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

#### **Figure 7.**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

**S.No Independent** 

*IPLs in milli seconds, Rt – right, Lt – left.*

*Correlation of independent variables and IPLs in normal subjects.*

**Table 2.**

**variable**

**S.No Independent variable Dependent variable Ear r-value p-value** 1. Age (years) IPL I-III Rt 0.081 0.397

1 Age (years) IPL I-III Rt −0.571 0.084

2 BMI (sq.m) IPL I-III Rt 0.742 0.013

3 HbA1c (%) IPL I-III Rt −0.431 0.335

2. BMI (sq.m) IPL I-III Rt 0.095 0.321

3. HbA1c (%) IPL I-III Rt 0.274 0.003

Lt −0.002 0.978

Lt 0.032 0.737

Lt −0.052 0.590

Lt −0.008 0.931

Lt −0.008 0.931

Lt 0.210 0.027

Lt 0.210 0.027

Lt 0.121 0.208

Lt 0.296 0.001

IPL III-V Rt 0.057 0.550

**Dependent variable Ear r-value p-value**

IPL III-V Rt −0.737 0.014

IPL I-V Rt −0.705 0.022

IPL III-V Rt 0.523 0.121

IPL I-V Rt 0.549 0.100

IPL III-V Rt −0.436 0.208

IPL I-V Rt −0.392 0.263

Lt −0.523 0.121

Lt −0.499 0.142

Lt −0.733 0.015

Lt 0.215 0.550

Lt 0.471 0.170

Lt 0.496 0.145

Lt −0.355 0.314

Lt −0.282 0.430

Lt −0.354 0.315

IPL I-V Rt 0.062 0.516

IPL III-V Rt 0.095 0.321

IPL I-V Rt 0.274 0.003

IPL III-V Rt 0.130 0.176

IPL I-V Rt 0.296 0.001

**96**

**Table 3.**

*IPLs in milli seconds, Rt – right, Lt – left.*

*Correlation of independent variables and IPLs in all subjects.*

*Correlation of IPL I-III and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 8.**

*Correlation of IPL III-V and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 9.**

*Correlation of IPL I-V and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 10.**

*Correlation of IPL I-III and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

**99**

**Figure 12.**

**Figure 11.**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

*Correlation of IPL III-V and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*Correlation of IPL I-V and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

#### **Figure 11.**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

*Correlation of IPL I-V and age in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The* 

*Correlation of IPL I-III and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*'r' and P values are correlating WoHI and WHI right and left ear.*

**98**

**Figure 10.**

**Figure 9.**

*Correlation of IPL III-V and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 12.**

*Correlation of IPL I-V and BMI in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 13.**

*Correlation of IPL I-III and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

#### **Figure 14.**

*Correlation of IPL III-V and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

**101**

with BMI.

**Figure 15.**

tion with HbA1c.

**5. Discussion**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

the right ear of WoHI (P = 0.758) and WHI (P = 0.128) group and left ear of WHI (P = 0.377) group showed negative correlation with BMI. In IPL III-V, the right ear (P = 0.284) of WoHI group and left ear (P = 0.543) of WHI group showed negative correlation with BMI. In IPL I-V, the right ear (P = 0.179) of WoHI group and left ear (P = 0.443) of WHI group shows negative correlation

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

*Correlation of IPL I-V and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

The correlation of IPL I-III, III-V and I-V values and HbA1c for both the ears in WoHI and WHI groups were given in **Figures 13–15**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with HbA1c. In IPL I-III, left ear of WoHI group shows negative correlation with HbA1c (P = 0.277). In IPL III-V, right ear of WoHI group shows negative correlation with HbA1c (P = 0.755). In IPL I-V, WoHI group right (P = 0.392) and left (P = 0.910) ears shows negative correla-

The BAER is a simple, non-invasive procedure to detect early impairment of auditory nerve and auditory pathway even in the absence of specific symptoms in the diabetic patients. The present study strongly recommended that BAER is carried out in all diabetic patients to detect the involvement of central neuronal pathway and periodic evaluation in of diabetes for early intervention regarding metabolic regulations.

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

#### **Figure 15.**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

*Correlation of IPL I-III and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment.* 

*Correlation of IPL III-V and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing* 

*impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

*The 'r' and P values are correlating WoHI and WHI right and left ear.*

**100**

**Figure 14.**

**Figure 13.**

*Correlation of IPL I-V and HbA1c in type 2 diabetes, without (WoHI) and with (WHI) hearing impairment. The 'r' and P values are correlating WoHI and WHI right and left ear.*

the right ear of WoHI (P = 0.758) and WHI (P = 0.128) group and left ear of WHI (P = 0.377) group showed negative correlation with BMI. In IPL III-V, the right ear (P = 0.284) of WoHI group and left ear (P = 0.543) of WHI group showed negative correlation with BMI. In IPL I-V, the right ear (P = 0.179) of WoHI group and left ear (P = 0.443) of WHI group shows negative correlation with BMI.

The correlation of IPL I-III, III-V and I-V values and HbA1c for both the ears in WoHI and WHI groups were given in **Figures 13–15**. In both the groups IPL I-III, III-V and I-V values were not statistically correlated with HbA1c. In IPL I-III, left ear of WoHI group shows negative correlation with HbA1c (P = 0.277). In IPL III-V, right ear of WoHI group shows negative correlation with HbA1c (P = 0.755). In IPL I-V, WoHI group right (P = 0.392) and left (P = 0.910) ears shows negative correlation with HbA1c.

#### **5. Discussion**

The BAER is a simple, non-invasive procedure to detect early impairment of auditory nerve and auditory pathway even in the absence of specific symptoms in the diabetic patients. The present study strongly recommended that BAER is carried out in all diabetic patients to detect the involvement of central neuronal pathway and periodic evaluation in of diabetes for early intervention regarding metabolic regulations.

The inter peak latencies of BAER tells about the time required for processing from one site to the next site in the auditory pathway [11]. In the present study, WHI group IPL I-III, III-V and I-V of both ears and left ear IPL III-V increased when compared to the normal subjects and WoHI group. These findings are in line with the previous research who found significant changes in the IPLs of the diabetics when compared to the controls [7, 12–16].

The prolongation of IPLs I-III, III-V and I-V are indicated central conduction delay at the level of brainstem and midbrain in the auditory pathway of diabetics. These prolongations are due to neuropathy at brainstem and midbrain level. These findings are supported by previous research [16]. In the present study, WHI group left ear IPL I-V values are decreased minimally when compared to WoHI group left ear IPL I-V values. Metformin (N, N-dimethylbiguanidine) is a widely used oral hypoglycaemic agent in T2DM; it has a potential anti-ototoxic activity. It prevents oxidative stress induced cell death and inhibition of lipid peroxidation and also scavenges hydroxyl radicals by modulating NADPH oxidase and inhibits apoptotic cascades by increasing the expression of the anti-apoptotic protein Bcl-2 [17]. This is the probable mechanism responsible for the reduced IPL values in the WHI group who are on metformin treatment.

The IPLs I-III, III-V and I-V of both the ears in WoHI and WHI groups were not correlated with the age, BMI and HbA1c values. The present study is contradicting with the previous research [18]. The HbA1c values are not correlated with the IPLs of both ears in WoHI and WHI groups. This finding is in line with the previous research [19–21] and contradicting with other studies [7]. In diabetes, hyperglycaemia results many pathological changes in nervous tissue by apoptosis, nerve energy deficits, intracellular calcium excitotoxicity, glycosylated products, oxidative stress, hypoxia and ischemia [22]. In the peripheral nervous system the myelin sheath and other nerve components are affected by hyperglycaemia [23].

In the present study, BMI and HbA1c values were correlated with the IPL I-III and I-V of both the ears in all subjects; it indicated that, with increase in BMI and HbA1c values the IPL values are increased in diabetic subjects. This finding is in line with the previous research where inter peak latencies were prolonged in uncontrolled T2DM subjects [24]. The inter peak latencies were prolonged in T2DM patients with duration of diabetes more than 7 years [24].

In diabetic neuropathy, hyperglycaemia accumulates diacylglycerol and activates PKC; this PKC causes transcription changes in the contractile proteins fibronectin, type IV collagen, and extracellular matrix (ECM) proteins in neurons and endothelial cells [25]. Due to this the affected neurons had degenerated axons, so that the amplitude of the neural conduction alters and the conduction velocity decreases in that affected nerves [26]. This is one of the reason to increase the inter peak latencies in the hearing impaired persons with T2DM in the present study. The present study is in line with the previous research with prolonged inter peak latencies in the T2DM patients [27, 28]. Another mechanism involved in the reduced neural transmission in T2DM with hyperglycaemia is oxidative stress with reactive oxygen species, these causes dendritic damage in the affected neurons with microglial activation [28–31] with prolongation of inter peak latencies.

Diabetes associated disruption between insulin activity and glucose metabolism results in decreased cerebral blood flow and oxidative glucose metabolism with impairment of neurotransmission. Diabetes has been widely associated with slowly progressive end-organ damage in brain resulting in diabetic neuropathy and/or mild to moderately impair cognitive function, both in type 1 and type 2 diabetic patients. The molecular mechanisms involved in the CNS damage in diabetes are hypothesized that AGEs formation, aldose reductase activity, oxidative stress, activation of protein kinase C and increased hexosamine pathway flux [32].

**103**

hearing loss.

**Acknowledgements**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

Chronic hyperglycaemia elicits pathophysiological changes to the nervous system as a result of oxidative stress, nerve energy deficits, decreased Na/K/ATPase activity and decreased neurotrophism. The damage to myelin sheaths and other nerve components as a result of hyperglycaemia occurs prominently in the peripheral nervous system but also in the spinal cord, cranial, optic and vestibular nerves. In the peripheral nervous system major myelin proteins are glycosylated, perhaps making them more prone to the effects of AGE, while in the CNS major myelin proteins are not glycosylated. The glial margin demarcates the boundary of the peripheral and central auditory systems, and is located about halfway between the cochlea and the cochlear nucleus [33]. These findings may explain why the peripheral auditory function was more affected than the central auditory nervous system in the present study. In diabetics, the IPLs I-III and I-V were positively correlated with autonomic score and large sensory nerve dysfunction. The abnormalities of waves III and V indicated an impairment of the auditory brainstem function in

The T2DM affects the cognitive function. The higher concentrations of neuron

The present study explains about the inter peak latency changes of the brainstem auditory evoked potentials in T2DM. BAER was performed in normal subjects, WoHI and WHI groups for both the ears. Compared the inter peak latencies I-III, III-V and I-V between normal subjects, WoHI and WHI groups. Correlated age, BMI and HbA1c values with inter peak latencies in normal subjects, WoHI and WHI groups for both the ears. Age, BMI and HbA1c are not correlated with increase in inter peak latencies for both the ears in WHI group. The BMI and HbA1c

We focused on functional changes but not anatomical changes. Because, functional changes can happen without any visible anatomical changes. For the assessment of structural changes we need CT or MRI brain which are highly cost, time consuming, radio-hazard and the subject may face inconvenience. However BAER can overcome all these circumstances. India is a country with large number of population with diabetes, insists the necessity to focus on long term hearing loss among them. BAER test is the very feasible method to perform at regular intervals for record. It could help to take necessary action to prevent

Research reported in this publication was conducted by scholars at the Fogarty International Center of the NIH training program under Award Number D43 TW 009078. The content is solely the responsibility of the authors and does not neces-

sarily represent the official views of the National Institute of Health.

specific enolase (NSE) protein in long standing T2DM result permanent brain damage and was correlated with poor cognitive performance. Its concentration increased by oxidative stress and neuronal apoptosis and these changes reversed with insulin treatment [35]. In T2DM, the P300 event related potentials (ERPs) revealed early cognitive dysfunction which was not detected by neuro-psychometric test mini mental state examination (MMSE) and it was more prominent when the disease duration more than 5 years. When the T2DM is associated with hyper-

tension, further increases the risk of cognitive impairment [36].

values were correlated with IPL I-V of both the ears in all subjects.

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

diabetic neuropathy [34].

**6. Conclusion**

#### *Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

Chronic hyperglycaemia elicits pathophysiological changes to the nervous system as a result of oxidative stress, nerve energy deficits, decreased Na/K/ATPase activity and decreased neurotrophism. The damage to myelin sheaths and other nerve components as a result of hyperglycaemia occurs prominently in the peripheral nervous system but also in the spinal cord, cranial, optic and vestibular nerves. In the peripheral nervous system major myelin proteins are glycosylated, perhaps making them more prone to the effects of AGE, while in the CNS major myelin proteins are not glycosylated. The glial margin demarcates the boundary of the peripheral and central auditory systems, and is located about halfway between the cochlea and the cochlear nucleus [33]. These findings may explain why the peripheral auditory function was more affected than the central auditory nervous system in the present study. In diabetics, the IPLs I-III and I-V were positively correlated with autonomic score and large sensory nerve dysfunction. The abnormalities of waves III and V indicated an impairment of the auditory brainstem function in diabetic neuropathy [34].

The T2DM affects the cognitive function. The higher concentrations of neuron specific enolase (NSE) protein in long standing T2DM result permanent brain damage and was correlated with poor cognitive performance. Its concentration increased by oxidative stress and neuronal apoptosis and these changes reversed with insulin treatment [35]. In T2DM, the P300 event related potentials (ERPs) revealed early cognitive dysfunction which was not detected by neuro-psychometric test mini mental state examination (MMSE) and it was more prominent when the disease duration more than 5 years. When the T2DM is associated with hypertension, further increases the risk of cognitive impairment [36].

#### **6. Conclusion**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

when compared to the controls [7, 12–16].

who are on metformin treatment.

The inter peak latencies of BAER tells about the time required for processing from one site to the next site in the auditory pathway [11]. In the present study, WHI group IPL I-III, III-V and I-V of both ears and left ear IPL III-V increased when compared to the normal subjects and WoHI group. These findings are in line with the previous research who found significant changes in the IPLs of the diabetics

The prolongation of IPLs I-III, III-V and I-V are indicated central conduction delay at the level of brainstem and midbrain in the auditory pathway of diabetics. These prolongations are due to neuropathy at brainstem and midbrain level. These findings are supported by previous research [16]. In the present study, WHI group left ear IPL I-V values are decreased minimally when compared to WoHI group left ear IPL I-V values. Metformin (N, N-dimethylbiguanidine) is a widely used oral hypoglycaemic agent in T2DM; it has a potential anti-ototoxic activity. It prevents oxidative stress induced cell death and inhibition of lipid peroxidation and also scavenges hydroxyl radicals by modulating NADPH oxidase and inhibits apoptotic cascades by increasing the expression of the anti-apoptotic protein Bcl-2 [17]. This is the probable mechanism responsible for the reduced IPL values in the WHI group

The IPLs I-III, III-V and I-V of both the ears in WoHI and WHI groups were not correlated with the age, BMI and HbA1c values. The present study is contradicting with the previous research [18]. The HbA1c values are not correlated with the IPLs of both ears in WoHI and WHI groups. This finding is in line with the previous research [19–21] and contradicting with other studies [7]. In diabetes, hyperglycaemia results many pathological changes in nervous tissue by apoptosis, nerve energy deficits, intracellular calcium excitotoxicity, glycosylated products, oxidative stress, hypoxia and ischemia [22]. In the peripheral nervous system the myelin sheath and

In the present study, BMI and HbA1c values were correlated with the IPL I-III and I-V of both the ears in all subjects; it indicated that, with increase in BMI and HbA1c values the IPL values are increased in diabetic subjects. This finding is in line with the previous research where inter peak latencies were prolonged in uncontrolled T2DM subjects [24]. The inter peak latencies were prolonged in T2DM

In diabetic neuropathy, hyperglycaemia accumulates diacylglycerol and activates PKC; this PKC causes transcription changes in the contractile proteins fibronectin, type IV collagen, and extracellular matrix (ECM) proteins in neurons and endothelial cells [25]. Due to this the affected neurons had degenerated axons, so that the amplitude of the neural conduction alters and the conduction velocity decreases in that affected nerves [26]. This is one of the reason to increase the inter peak latencies in the hearing impaired persons with T2DM in the present study. The present study is in line with the previous research with prolonged inter peak latencies in the T2DM patients [27, 28]. Another mechanism involved in the reduced neural transmission in T2DM with hyperglycaemia is oxidative stress with reactive oxygen species, these causes dendritic damage in the affected neurons with microglial

Diabetes associated disruption between insulin activity and glucose metabolism results in decreased cerebral blood flow and oxidative glucose metabolism with impairment of neurotransmission. Diabetes has been widely associated with slowly progressive end-organ damage in brain resulting in diabetic neuropathy and/or mild to moderately impair cognitive function, both in type 1 and type 2 diabetic patients. The molecular mechanisms involved in the CNS damage in diabetes are hypothesized that AGEs formation, aldose reductase activity, oxidative stress, activation of

other nerve components are affected by hyperglycaemia [23].

patients with duration of diabetes more than 7 years [24].

activation [28–31] with prolongation of inter peak latencies.

protein kinase C and increased hexosamine pathway flux [32].

**102**

The present study explains about the inter peak latency changes of the brainstem auditory evoked potentials in T2DM. BAER was performed in normal subjects, WoHI and WHI groups for both the ears. Compared the inter peak latencies I-III, III-V and I-V between normal subjects, WoHI and WHI groups. Correlated age, BMI and HbA1c values with inter peak latencies in normal subjects, WoHI and WHI groups for both the ears. Age, BMI and HbA1c are not correlated with increase in inter peak latencies for both the ears in WHI group. The BMI and HbA1c values were correlated with IPL I-V of both the ears in all subjects.

We focused on functional changes but not anatomical changes. Because, functional changes can happen without any visible anatomical changes. For the assessment of structural changes we need CT or MRI brain which are highly cost, time consuming, radio-hazard and the subject may face inconvenience. However BAER can overcome all these circumstances. India is a country with large number of population with diabetes, insists the necessity to focus on long term hearing loss among them. BAER test is the very feasible method to perform at regular intervals for record. It could help to take necessary action to prevent hearing loss.

#### **Acknowledgements**

Research reported in this publication was conducted by scholars at the Fogarty International Center of the NIH training program under Award Number D43 TW 009078. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Rajesh Paluru\* and Devendra Singh Negi Department of Physiology, MediCiti Institute of Medical Sciences, Ghanpur, Telangana, India

\*Address all correspondence to: drrajeshpaluru@gmail.com

© 2021 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.

**105**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

CoDAS. 2014; 26(2): 117-121. DOI: 10.1590/2317-1782/2014469in

[9] Schmidt RJ, Sataloff RT and Newman J. The sensitivity of auditory brainstemresponse testing for the diagnosis of acoustic neuromas. Arch. Otolaryngol. Head & Neck Surg. 2001;

127(1):19-22. DOI:10.1001/

[10] Berger JR and Blum AS. Brainstem Auditory Evoked Potentials. In A. S. Blum & S. B. Rutkove (Eds.). The Clinical Neurophysiology Primer. Totowa: Humana Press Inc. 2006; pp:

[11] Goyal GL and Anjana Mittal. Effect of elevated mean arterial pressure (MAP) and pulse pressure (PP) on auditory brainstem responses. Sch. J. App. Med. Sci. 2015; 3(3B): 1117-1120.

[12] Bayazit Y, Yilmaz M, Kepekçi Y, Mumbuç S and Kanlikama M. Use of the auditory brainstem response testing in the clinical evaluation of the patients with diabetes mellitus. J. Neurol. Sci. 2000; 181(1-2): 29-32. DOI: 10.1016/

[13] Sharma R, Gupta SC, Tyagi I, Kumar S and Mukherjee K. Brain stem evoked responses in patients with diabetes mellitus. Indian J Otolaryngol Head Neck Surg. 2000; 52(3): 223-229.

[14] Al-Azzawi LM and Mirza KB. The usefulness of the brainstem auditory evoked potential in the early diagnosis of cranial nerve neuropathy associated with diabetes mellitus. Electromyogr Clin Neurophysiol. 2004; 44(7): 387-

[15] Durmus C, Yetiser S and Durmus O. Auditory brainstem evoked responses in insulin-dependent (ID) and noninsulin-dependent (NID) diabetic

s0022-510x(00)00400-7

DOI: 10.1007/BF03006189

394. PMID: 15559072.

archotol.127.1.19

475-484.

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

[1] Tama'ST. VA'Rkonyi, Ferenc To'Th, LÁ SzlÓ RovÓ, Csaba Lengyel, JÓ Zsef Ge'Za Kiss and Pe'Ter Kempler et al. Impairment of the auditory brainstem function in diabetic neuropathy. Diabetes Care. 2002; 25(3): 631-632. DOI: doi:10.2337/diacare.25.3.631

**References**

[2] Daniel Porte Jr, Denis G. Baskin and Michael W. Schwartz. Insulin signalling in the central nervous system: A critical role in metabolic homeostasis and disease from *C. elegans* to humans. Diabetes. 2005; 54(5): 1264-1276. DOI:

https://doi.org/10.2337/ diabetes.54.5.1264

Baylor University; 2013.

UK. 2006; pp: 309. **ISBN**: 978-0-12-372519-6.

PMID: 21448408

8210.122629

2005; 42(1): 209-221.

[3] Devyn Lambell. The auditory brainstem response: History and future in medicine (thesis)., Waco, Texas:

[4] Aage R. Møller. Hearing: Anatomy, Physiology, and Disorders of the Auditory System. 2nd edn, Elsevier Inc,

[5] Gupta R, Aslam M, Hasan SA and Siddiqi SS. Type 2 diabetes mellitus and auditory brainstem responses - a hospital based study. Indian J Endocrinol Metab. 2010; 14(1): 9-11.

[6] Siddiqi SS, Gupta R, Aslam M, Hasan SA and Khan SA. Type 2 diabetes mellitus and auditory brainstem response. Indian J Endocr Metab. 2013; 17: 1073-1077. DOI: 10.4103/2230-

[7] Fawi GH, Khalifa GA and Kasim MA. Central and peripheral conduction abnormalities in diabetes mellitus. Egypt J. Neurol. Psychiat. Neurosurg.

[8] Rosa LAC, Suzuki MR, Angrisani RG and Azevedo MF. Auditory brainstem response: reference-values for age.

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

#### **References**

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

The authors declare no conflict of interest.

**Conflict of interest**

**104**

**Author details**

Ghanpur, Telangana, India

Rajesh Paluru\* and Devendra Singh Negi

provided the original work is properly cited.

Department of Physiology, MediCiti Institute of Medical Sciences,

© 2021 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: drrajeshpaluru@gmail.com

[1] Tama'ST. VA'Rkonyi, Ferenc To'Th, LÁ SzlÓ RovÓ, Csaba Lengyel, JÓ Zsef Ge'Za Kiss and Pe'Ter Kempler et al. Impairment of the auditory brainstem function in diabetic neuropathy. Diabetes Care. 2002; 25(3): 631-632. DOI: doi:10.2337/diacare.25.3.631

[2] Daniel Porte Jr, Denis G. Baskin and Michael W. Schwartz. Insulin signalling in the central nervous system: A critical role in metabolic homeostasis and disease from *C. elegans* to humans. Diabetes. 2005; 54(5): 1264-1276. DOI: https://doi.org/10.2337/ diabetes.54.5.1264

[3] Devyn Lambell. The auditory brainstem response: History and future in medicine (thesis)., Waco, Texas: Baylor University; 2013.

[4] Aage R. Møller. Hearing: Anatomy, Physiology, and Disorders of the Auditory System. 2nd edn, Elsevier Inc, UK. 2006; pp: 309. **ISBN**: 978-0-12-372519-6.

[5] Gupta R, Aslam M, Hasan SA and Siddiqi SS. Type 2 diabetes mellitus and auditory brainstem responses - a hospital based study. Indian J Endocrinol Metab. 2010; 14(1): 9-11. PMID: 21448408

[6] Siddiqi SS, Gupta R, Aslam M, Hasan SA and Khan SA. Type 2 diabetes mellitus and auditory brainstem response. Indian J Endocr Metab. 2013; 17: 1073-1077. DOI: 10.4103/2230- 8210.122629

[7] Fawi GH, Khalifa GA and Kasim MA. Central and peripheral conduction abnormalities in diabetes mellitus. Egypt J. Neurol. Psychiat. Neurosurg. 2005; 42(1): 209-221.

[8] Rosa LAC, Suzuki MR, Angrisani RG and Azevedo MF. Auditory brainstem response: reference-values for age.

CoDAS. 2014; 26(2): 117-121. DOI: 10.1590/2317-1782/2014469in

[9] Schmidt RJ, Sataloff RT and Newman J. The sensitivity of auditory brainstemresponse testing for the diagnosis of acoustic neuromas. Arch. Otolaryngol. Head & Neck Surg. 2001; 127(1):19-22. DOI:10.1001/ archotol.127.1.19

[10] Berger JR and Blum AS. Brainstem Auditory Evoked Potentials. In A. S. Blum & S. B. Rutkove (Eds.). The Clinical Neurophysiology Primer. Totowa: Humana Press Inc. 2006; pp: 475-484.

[11] Goyal GL and Anjana Mittal. Effect of elevated mean arterial pressure (MAP) and pulse pressure (PP) on auditory brainstem responses. Sch. J. App. Med. Sci. 2015; 3(3B): 1117-1120.

[12] Bayazit Y, Yilmaz M, Kepekçi Y, Mumbuç S and Kanlikama M. Use of the auditory brainstem response testing in the clinical evaluation of the patients with diabetes mellitus. J. Neurol. Sci. 2000; 181(1-2): 29-32. DOI: 10.1016/ s0022-510x(00)00400-7

[13] Sharma R, Gupta SC, Tyagi I, Kumar S and Mukherjee K. Brain stem evoked responses in patients with diabetes mellitus. Indian J Otolaryngol Head Neck Surg. 2000; 52(3): 223-229. DOI: 10.1007/BF03006189

[14] Al-Azzawi LM and Mirza KB. The usefulness of the brainstem auditory evoked potential in the early diagnosis of cranial nerve neuropathy associated with diabetes mellitus. Electromyogr Clin Neurophysiol. 2004; 44(7): 387- 394. PMID: 15559072.

[15] Durmus C, Yetiser S and Durmus O. Auditory brainstem evoked responses in insulin-dependent (ID) and noninsulin-dependent (NID) diabetic

subjects with normal hearing. Int J Audiol. 2004; 43(1): 29-33. DOI: 10.1080/14992020400050005

[16] Mahallik D, Sahu P and Mishra R. Evaluation of auditory brainstem evoked response in middle aged type 2 diabetes mellitus with normal hearing subjects. Indian J Otol. 2014; 20(4): 199-202. DOI: 10.4103/0971-7749.14693

[17] Oishi N, Kendall A and Schacht J. Metformin protects against gentamicininduced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett. 2014; 583: 65-69. DOI: 10.1016/j. neulet.2014.09.028

[18] Akinpelu OV, Mujica-Mota M and Daniel SJ. Is type 2 diabetes mellitus associated with alterations in hearing? A systematic review and meta-analysis. Laryngoscope. 2014; 2124(3): 767-776. DOI: 10.1002/lary.24354

[19] Dolu H, Ulas UH, Bolu E, Ozkardes A, Odabasi Z and Ozata M. Evaluation of central neuropathy in type II diabetes mellitus by multimodal evoked potentials. Acta neurol. Belg. 2003; 103(4): 206-211. PMID: 15008505

[20] Díaz de León-Morales LV, Jáuregui-Renaud K, Garay-Sevilla ME, Hernández-Prado J and Malacara-Hernández JM. Auditory impairment in patients with type 2 diabetes mellitus. Arch Med Res. 2005; 36 (5): 507-510. DOI: 10.1016/j. arcmed.2005.02.002

[21] Talebi M, Moosavi M, Mohamadzade NA and Mogadam R. Study on brainstem auditory evoked potentials in diabetes Mellitus. Neurosciences (Riyadh). 2008; 13(4): 370-373. PMID: 21063364

[22] Gries FA, Cameron NE, Low PA and Ziegler D. Textbook of diabetic neuropathy. Stuttgart, Germany: Thieme. 2003; pp: 208-17.

[23] Mizisin A and Powell H. Pathogenesis and pathology of diabetic neuropathy. In F Arnold Gries, Norman E Cameron (Eds.). Textbook of diabetic neuropathy. Stuttgart, Germany: Thieme. 2003; 83-169.

[24] Sushil MI, Muneshwar JN and Afroz S. To study brain stem auditory evoked potential in patients with type 2 diabetes mellitus- a cross sectional comparative study. JCDR. 2016; 10(11): CC01-CC04. DOI: 10.7860/ JCDR/2016/19336.8791

[25] Powers AC. Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds*.* Harrison's Principles of Internal Medicine, 19th edn, vol 2*.* New York, NY: McGraw-Hill. 2015b; pp: 2770.

[26] David LZd, Finamor MM and Buss C. Possible hearing implications of diabetes mellitus: a literature review. Rev. CEFAC. 2015; 17(6): 2018-2024.

[27] Vaughan N, James K, McDermott D, Griest S and Fausti S. Auditory brainstem response differences in diabetic and non-diabetic veterans. J Am Acad Audiol. 2007; 18(10): 863-871. DOI: 10.3766/jaaa.18.10.5

[28] Helzner EP and Contrera KJ. Type 2 Diabetes and hearing impairment. Curr. Diab. Rep. 2016; 16(1): 1-7. DOI: 10.1007/s11892-015-0696-0

[29] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865): 813-820. DOI: 10.1038/414813a

[30] Sonneville R, den Hertog HM, Güiza F, Gunst J, Derese I and Wouters PJ et al. Impact of Hyperglycemia on Neuropathological Alterations during Critical Illness. J. Clin. Endocrinol. Metab. 2012; 97(6): 2113-2123. DOI: https://doi.org/10.1210/jc.2011-2971

**107**

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus*

*DOI: http://dx.doi.org/10.5772/intechopen.97469*

[31] Hinder LM, Vincent AM, Burant CF,

Pennathur S and Feldman EL. Bioenergetics in diabetic neuropathy: what we need to know. J.Peripher. Nerv. Syst. 2012; 17(Suppl 2): 10-14. DOI: 10.1111/j.1529-8027.2012.00389.x

[32] Duarte AI, Moreira PI and

org/10.1155/2012/384017

10.1016/j.heares.2005.09.002

[34] Va'rkonyi TT, To'th F, Rovo´ L, Lengyel C, Kiss JZ, Kempler P and Lonovics J. Impairment of the Auditory

Brainstem Function in Diabetic

[35] Hamed SA, Elaal RFA, Mohamad KA, Youssef AH and Abdou MA. Neuropsychological, neurophysiological and laboratory markers of direct brain injury in type 2 diabetes mellitus. Journal of Neurology and Neuroscience. 2012; 3(1:2): 1-11.

diacare.25.3.631

ijdm.2011.01.001

Neuropathy. Diabetes Care. 2002; 25(3): 631-632. DOI: https://doi.org/10.2337/

[36] Hazari MAH, Reddy BR, Uzma N and Kumar BS. Cognitive impairment in type 2 diabetes mellitus. International Journal of Diabetes Mellitus. 2015; 3: 19-24 DOI: https://doi.org/10.1016/j.

Oliveira CR. Insulin in central nervous system: More than just a peripheral hormone. Journal of Aging Research. 2012; vol 2012: 1-22. DOI: https://doi.

[33] Frisina ST, Mapes F, Kim S, Frisina DR and Frisina RD. Characterization of hearing loss in aged type II diabetics. Hear Res. 2006; 211(1-2): 103-113. DOI:

*Brainstem Auditory Evoked Potentials in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97469*

[31] Hinder LM, Vincent AM, Burant CF, Pennathur S and Feldman EL. Bioenergetics in diabetic neuropathy: what we need to know. J.Peripher. Nerv. Syst. 2012; 17(Suppl 2): 10-14. DOI: 10.1111/j.1529-8027.2012.00389.x

*Hearing Loss - From Multidisciplinary Teamwork to Public Health*

[23] Mizisin A and Powell H.

Thieme. 2003; 83-169.

Pathogenesis and pathology of diabetic neuropathy. In F Arnold Gries, Norman E Cameron (Eds.). Textbook of diabetic neuropathy. Stuttgart, Germany:

[24] Sushil MI, Muneshwar JN and Afroz S. To study brain stem auditory evoked potential in patients with type 2 diabetes mellitus- a cross sectional comparative study. JCDR. 2016; 10(11):

[25] Powers AC. Diabetes Mellitus: Diagnosis, Classification, and

Hauser S, Longo D, Jameson J,

York, NY: McGraw-Hill. 2015b;

[26] David LZd, Finamor MM and Buss C. Possible hearing implications of diabetes mellitus: a literature review. Rev. CEFAC. 2015; 17(6): 2018-2024.

Griest S and Fausti S. Auditory brainstem response differences in diabetic and non-diabetic veterans. J Am Acad Audiol. 2007; 18(10): 863-871.

DOI: 10.3766/jaaa.18.10.5

[27] Vaughan N, James K, McDermott D,

[28] Helzner EP and Contrera KJ. Type 2 Diabetes and hearing impairment. Curr.

Diab. Rep. 2016; 16(1): 1-7. DOI: 10.1007/s11892-015-0696-0

[29] Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414(6865):

[30] Sonneville R, den Hertog HM, Güiza F, Gunst J, Derese I and Wouters PJ et al. Impact of Hyperglycemia on Neuropathological Alterations during Critical Illness. J. Clin. Endocrinol. Metab. 2012; 97(6): 2113-2123. DOI: https://doi.org/10.1210/jc.2011-2971

813-820. DOI: 10.1038/414813a

pp: 2770.

Pathophysiology. In: Kasper D, Fauci A,

Loscalzo J. eds*.* Harrison's Principles of Internal Medicine, 19th edn, vol 2*.* New

CC01-CC04. DOI: 10.7860/ JCDR/2016/19336.8791

subjects with normal hearing. Int J Audiol. 2004; 43(1): 29-33. DOI: 10.1080/14992020400050005

[16] Mahallik D, Sahu P and Mishra R. Evaluation of auditory brainstem evoked response in middle aged type 2 diabetes mellitus with normal hearing subjects. Indian J Otol. 2014; 20(4): 199-202. DOI: 10.4103/0971-7749.14693

[17] Oishi N, Kendall A and Schacht J. Metformin protects against gentamicininduced hair cell death in vitro but not ototoxicity in vivo. Neurosci Lett. 2014;

[18] Akinpelu OV, Mujica-Mota M and Daniel SJ. Is type 2 diabetes mellitus associated with alterations in hearing? A systematic review and meta-analysis. Laryngoscope. 2014; 2124(3): 767-776.

583: 65-69. DOI: 10.1016/j. neulet.2014.09.028

DOI: 10.1002/lary.24354

15008505

[19] Dolu H, Ulas UH, Bolu E,

[20] Díaz de León-Morales LV,

36 (5): 507-510. DOI: 10.1016/j.

[21] Talebi M, Moosavi M,

370-373. PMID: 21063364

Thieme. 2003; pp: 208-17.

Ziegler D. Textbook of diabetic neuropathy. Stuttgart, Germany:

Hernández-Prado J and

arcmed.2005.02.002

Jáuregui-Renaud K, Garay-Sevilla ME,

Malacara-Hernández JM. Auditory impairment in patients with type 2 diabetes mellitus. Arch Med Res. 2005;

Mohamadzade NA and Mogadam R. Study on brainstem auditory evoked potentials in diabetes Mellitus. Neurosciences (Riyadh). 2008; 13(4):

[22] Gries FA, Cameron NE, Low PA and

Ozkardes A, Odabasi Z and Ozata M. Evaluation of central neuropathy in type II diabetes mellitus by multimodal evoked potentials. Acta neurol. Belg. 2003; 103(4): 206-211. PMID:

**106**

[32] Duarte AI, Moreira PI and Oliveira CR. Insulin in central nervous system: More than just a peripheral hormone. Journal of Aging Research. 2012; vol 2012: 1-22. DOI: https://doi. org/10.1155/2012/384017

[33] Frisina ST, Mapes F, Kim S, Frisina DR and Frisina RD. Characterization of hearing loss in aged type II diabetics. Hear Res. 2006; 211(1-2): 103-113. DOI: 10.1016/j.heares.2005.09.002

[34] Va'rkonyi TT, To'th F, Rovo´ L, Lengyel C, Kiss JZ, Kempler P and Lonovics J. Impairment of the Auditory Brainstem Function in Diabetic Neuropathy. Diabetes Care. 2002; 25(3): 631-632. DOI: https://doi.org/10.2337/ diacare.25.3.631

[35] Hamed SA, Elaal RFA, Mohamad KA, Youssef AH and Abdou MA. Neuropsychological, neurophysiological and laboratory markers of direct brain injury in type 2 diabetes mellitus. Journal of Neurology and Neuroscience. 2012; 3(1:2): 1-11.

[36] Hazari MAH, Reddy BR, Uzma N and Kumar BS. Cognitive impairment in type 2 diabetes mellitus. International Journal of Diabetes Mellitus. 2015; 3: 19-24 DOI: https://doi.org/10.1016/j. ijdm.2011.01.001

Section 4

Teamwork Approach to

Hearing Aids Innovations

**109**

Section 4
