If you have ever been prescribed medication, you may have been given a list of possible side effects. Oftentimes, those side effects include things such as fatigue, weight loss/weight gain, mood changes, and more. One lesser-known side effect of some medications is ototoxicity.
What is Ototoxicity?
Ototoxicity occurs when a person consumes medications or substances that are toxic to the ears. This article will discuss the topics related to ototoxicity: mechanisms of damage, signs and symptoms, diagnosis, treatment, and prevention.
Mechanisms of Ototoxicity
The inner ear (cochlea), a spiral-shaped structure within the auditory pathway, holds hundreds of thousands of cells that are responsible for picking up different frequencies (pitches). The human ear can detect frequencies between 20 Hz (very low pitch) and 20,000 Hz (very high pitch).
Just as a piano is arranged with low pitches on one end and high pitches on the other, the cochlea is arranged in a similar manner. The base of the cochlea, the portion that is closest to the outside environment, picks up the highest frequencies. Traveling towards the apical portion of the cochlea, deeper within the spiral, are the cells that pick up lower frequencies.
This is called tonotopic organization. Ototoxic damage typically begins at the base of the cochlea (impacting the high frequencies) and then progresses towards the apex (impacting the low frequencies) [6].
Medications such as platinum-based chemotherapies and aminoglycoside antibiotics enter the inner ear, preventing oxygenated blood from getting to cochlear cells [2]. Hypoxia (lack of oxygen to the tissues) can cause cell death or inflammation that leads to cell death. This is called excessive reactive oxygen species (ROS) in cochlear cells [7]. The extent of the cochlear cell death with platinum-based chemotherapies is generally dose-dependent, meaning higher doses cause more damage. Cochlear cells cannot be regenerated. Therefore, cell death is permanent and irreversible.
Loop diuretics shift the levels of fluid in the body, and the inner ear is a fluid-filled structure. Ototoxicity related to loop diuretics is often associated with that fluid and electrolyte shift, which causes swelling of the inner ear [4].
What Substances Can Cause Ototoxicity?
While there are over 600 known categories of drugs that can cause ototoxicity, three most common causes are platinum based chemotherapies, aminoglycoside antibiotics, and loop diuretics [3].
Platinum based chemotherapies are often used to treat cancer that impacts different parts of the body, such as the head and neck, lungs, ovaries, bladder, and more. Children are commonly given platinum based chemotherapies to treat neuroblastoma, osteosarcoma, and hepatoblastoma. Three common types of platinum based therapy are cisplatin, carboplatin, and oxaliplatin, with the most common being cisplatin. This is due to the effectiveness of the drug, survivability post-treatment, and how many cancers it can treat [4].
Aminoglycosides are broad-spectrum antibiotics that can be used for gram-negative infections. The most common aminoglycoside antibiotics include tobramycin, gentamicin, and amikacin. These medications are commonly used to treat sepsis, a life-threatening infection that can lead to septic shock, causing death. Individuals with cystic fibrosis are often prescribed aminoglycoside antibiotics to treat frequent respiratory infections [5]. Loop diuretics aim to control and manage fluid associated with congestive heart failure, liver cirrhosis, and renal (kidney) disease [6].
How Common is Ototoxicity?
The reported occurrence of ototoxicity caused by ototoxic medications varies significantly between studies and publications. One meta-analysis reports that the reported occurrence of ototoxicity is between 4% to 90% [4]. The author of the meta-analysis suggests that this variability is related to cumulative dosages of ototoxic medications and the age of the patient receiving these medications. Related to cisplatin-induced ototoxicity, age can play a part in a person’s susceptibility.
One study suggests that in adults, 23% to 50% undergoing treatment with cisplatin develop ototoxicity, while up to 60% of children receiving cisplatin therapy develop ototoxicity [3]. Another study suggests that 22% to 77% of children undergoing cisplatin therapy develop ototoxicity [7]. For aminoglycoside antibiotics, ototoxicity occurs in up to 63% of patients. Loop diuretics such as furosemide cause ototoxicity in up to 6% to 7% of patients.
Again, there is significant variability in reported ototoxicity. Hearing loss and tinnitus are the most common symptoms of ototoxicity. A cohort with over 80 patients (mean age of 26 years) undergoing cisplatin therapy was surveyed. In this study, ototoxicity was present in 20% of patients. Within that 20% of patients, 59% reported tinnitus, 18% reported hearing loss, and 23% reported both. 81% of patients with ototoxicity presented with symptoms in both ears (bilaterally) [4].
Signs & Symptoms of Ototoxicity
The most common symptoms of ototoxicity include hearing loss, tinnitus, and dizziness/vertigo [3]. The onset of ototoxicity symptoms can be days to months after treatment has been administered. Due to this, ototoxicity monitoring is essential [6]. Ototoxicity monitoring will be discussed later in the article.
To provide the necessary background, speech sounds will now be discussed. Different speech sounds contain different frequencies. Vowel sounds such as “a” and “o” and voiced consonants such as “z” and “v” are made up of lower frequencies. Unvoiced consonants such as “sh” or “s” are made up of high frequencies [4].
In general, the low frequencies provide the volume of speech, while the high frequencies are related to the clarity of speech. The impact of ototoxic medications damaging the cells that pick up high frequencies would lead to high-frequency hearing loss.
A person with high-frequency hearing loss may report that people sound as if they are “mumbling” or report difficulty understanding speech in background noise. They may state that they can hear someone speaking, they just cannot understand what is being said. Again, this is due to the lack of access to high-frequency speech sounds that provide clarity of speech.
Young children undergoing treatment that includes ototoxic medications that result in hearing loss are at risk for communication difficulties and a delay in language acquisition. As previously mentioned, ototoxic medications typically begin damaging the cells in the cochlea that pick up high frequencies and progress to impact low frequencies.
Children that develop hearing loss prior to, or during, language development may not be able to hear different speech sounds. High-frequency speech sounds such as “th” and “s” are essential for speech discrimination. Children unable to hear those speech sounds may think of speech as unintelligible. A large portion of language development in children is repeating words that they can hear.
If a child with a high-frequency hearing loss is unable to discriminate between the speech that they are hearing, their own speech may be unintelligible. Additionally, that child’s vocabulary can be significantly more limited than that of a child without hearing loss [4].
Another common symptom of ototoxicity is tinnitus. Out of platinum-based chemotherapies, aminoglycoside antibiotics, and loop diuretics, tinnitus is most associated with chemotherapy [6].
Tinnitus is often reported as a ringing sound but can also be described as a buzzing or hissing sound. Tinnitus is often associated with hearing loss. This is because, even though there are different causes of tinnitus, the most popular theory of the origin of tinnitus is due to cochlear cell damage. The brain is constantly seeking out sensory stimulation. When the brain is deprived of stimulation (auditory stimulation), it may create its own stimulation (tinnitus). Dizziness and vertigo are other common symptoms of ototoxicity. Out of the three previously discussed classifications of ototoxic medications, aminoglycoside antibiotics, and loop diuretics are more likely than platinum-based therapies to cause dizziness and vertigo [6].
Ototoxicity: Diagnosis and Monitoring
The American Speech-Language-Hearing Association (ASHA) provides guidelines for speech-language pathologists and audiologists to follow for various clinical situations. ASHA’s guidelines for ototoxicity diagnosis and monitoring include the following: completing a comprehensive case history, performing an audiometric evaluation, testing extended high frequencies, and evaluating distortion product otoacoustic emissions (DPOAEs) [1].
If possible, a baseline audiometric evaluation should be completed prior to the administration of treatment. If this is not possible, the baseline should be completed within 24 hours of the administration of cisplatin-based therapies and 72 hours for aminoglycoside antibiotics [6]. Ototoxicity monitoring can be effective only when a fixed regimen is used. Between clinics, there is significant variation regarding the frequency of appointments for ototoxicity monitoring and the length of time that ototoxicity monitoring should be continued post-treatment.
As previously mentioned, the human ear can hear from 20 Hz to 20,000 Hz. Despite this, comprehensive hearing tests typically only test frequencies between 250 Hz to 8,000 Hz. This is because the speech sounds are made up of these frequencies.
Due to the fact that ototoxicity typically impacts the cochlear cells that pick up high frequencies, extended high frequencies should be evaluated during ototoxicity monitoring. Detecting damage to the cells that pick up the highest frequencies can assist in predicting further hearing loss [3].
When presented with specific tones at specific intensity (loudness) levels, functioning cells in the inner ear will give an “echo” that can be measured by equipment. This “echo” is called a distortion product otoacoustic emission (DPOAE). Similar to testing high frequencies, testing DPOAEs during ototoxicity monitoring can predict progressive hearing loss. Additionally, testing DPOAEs will give an objective result, while comprehensive hearing tests and testing the high frequencies will result in subjective results.
Objective tests do not require participation, while subjective tests require a patient’s behavioral response. Objective tests such as DPOAEs are essential when monitoring patients who cannot participate, such as infants or non-responsive adults [3].
Ototoxicity: Prevention and Treatment
Unfortunately, it is not always possible to prevent ototoxicity, even if the patient is being closely monitored by a team of medical professionals. The medications previously discussed are typically lifesaving, which takes precedence over hearing abilities [6].
There are limited studies investigating otoprotective methods. This is due to the lack of control groups and longitudinal studies, as well as the variation that comes with the use of ototoxic medications. Recently, clinical trials have explored otoprotective agents such as sodium thiosulfate, amifostine, and N-acetylcysteine used to prevent ototoxicity caused by cisplatin-induced hearing loss.
While many of these studies have indicated a reduction in cisplatin-induced hearing loss, the above-mentioned substances can also reduce the effectiveness of cisplatin therapy [3]. Currently, there are no drugs that have been approved by the US Food and Drug Administration to be used for the prevention of medication-induced ototoxicity.
Within the past two decades, different methods have been tested for cisplatin-induced ototoxicity. As described above, cisplatin can cause hypoxia and inflammation, leading to cell death in the inner ear. Recent animal studies suggest that antioxidants and anti-inflammatories can treat hypoxia and inflammation. However, similar to the previously mentioned protective substances, these anti-inflammatories, and antioxidants may reduce the long-term effectiveness of cisplatin [7].
How Long Can Ototoxicity Last?
The extent of the damage that ototoxic substances are capable of is extremely variable. However, the class of medication can determine the length that ototoxicity-induced hearing loss can last. Platinum-based chemotherapies commonly result in permanent hearing loss, while loop diuretics can result in transient or temporary hearing loss. As previously mentioned when discussing the mechanisms of ototoxicity, platinum-based chemotherapies often result in cochlear cell death. This cell death is permanent and irreversible because cochlear cells are unable to regenerate.
In contrast, loop diuretics are thought to cause shifts in the fluids and electrolytes of the cochlea, causing swelling of the inner ear. As the swelling declines, a person may regain some or all hearing abilities [4]. Despite the transient nature of hearing loss associated with loop diuretics, patients should still be monitored closely by a team of medical professionals.
What Can Help With Hearing Loss?
Patients with ototoxic-induced hearing loss have various options for treating and coping with hearing loss. The type of treatment is often dependent on an individual’s degree of hearing loss and other specific symptoms. The two most common treatments for hearing loss are hearing aids and cochlear implants.
Hearing aids are programmed based on a person’s degree (severity) of hearing loss, with those results typically obtained during a comprehensive hearing test. A comprehensive hearing test will record thresholds of frequencies that make up different speech sounds. The hearing aids provide more amplification (volume) in areas of hearing loss than areas without hearing loss. For example, a person with mild sensorineural hearing loss in the low frequencies that progresses to severe sensorineural hearing loss in the high frequencies will receive more amplification for high-frequency sounds than low-frequency sounds.
Untreated hearing loss can lead to a perceived poor quality of life and social isolation, which has the possibility to cause poor social and communication development [3]. As the goal of hearing aids is to improve speech understanding, individuals with hearing loss who use hearing aids are less likely to self-isolate than those with hearing loss who do not use hearing aids. The need for hearing aids is variable in those with ototoxicity. One study with 333 patients undergoing cisplatin or carboplatin treatment for neuroblastoma recorded the number of patients who required hearing aids post-treatment. 29% of patients with cisplatin treatment required hearing aids, and 58% of patients with carboplatin treatment required hearing aids [4].
When a person’s hearing loss becomes so severe that hearing aids are no longer beneficial, cochlear implants may be considered. As previously mentioned, we are unable to regenerate cochlear cells. When there are so few remaining cochlear cells left as a result of ototoxicity, the amount of volume a hearing aid can provide will never be enough to provide benefits such as speech understanding and sound awareness.
A cochlear implant involves the placement of an electrode array into the inner ear. Simply, the goal of a cochlear implant is for the electrode array to essentially “replace” the damaged/dead cochlear cells. Rather than the cochlea being stimulated acoustically (through natural hearing/hearing aids), a cochlear implant will stimulate the cochlea electronically (through the array).
Conclusion
To conclude, the three most common classes of medications that can cause ototoxicity are platinum-based chemotherapies, aminoglycoside antibiotics, and loop diuretics. The impact of ototoxicity is incredibly variable.
This variability can be impacted by the type of medication used, the dosage of medication, a patient’s age, and more. Patients undergoing treatment that may cause ototoxicity should be closely monitored by a team of medical professionals to track and possibly predict hearing loss.
The treatment of ototoxicity is also variable, with some patients not requiring hearing aids, those who require hearing aids, and those who no longer benefit from hearing aids and may require cochlear implantation.
References
- American Speech-Language-Hearing Association. (1994). Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. ASHA.
- Fu, X., Wan, P., Wang, J., Guo, S., Zhang, Y., An, Y., Ye, C., Gao, J., Yang, J., Fan, J., & Chai, R. (2021). Mechanism and prevention of ototoxicity induced by aminoglycosides. Frontiers in Cellular Neuroscience, 15.
- Ganesan, P., Schmiedge, J., Manchaiah, V., Swapna, S., Dhandayutham, S., & Kothandaraman, P. (2018). Ototoxicity: A challenge in diagnosis and treatment. Journal of Audiology and Otology, 22.
- Landier, W. (2016). Ototoxicity and cancer therapy. National Library of Medicine: Cancer.
- Laurell, G. (2019). Pharmacological intervention in the field of ototoxicity. HNO, 67.
- Ramma, L., Schellack, N., & Heinze, B. (2019). Prevention of treatment-induced ototoxicity: An update for clinicians. South African Medical Journal, 109.
- Sheth, S., Mukherjea, D., Rybak, L., & Ramkumar, V. (2017). Mechanisms of cisplatin-induced ototoxicity and otoprotection. Frontiers in Cellular Neuroscience, 11.
