Ototoxicity | |
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Specialty | Otorhinolaryngology |
Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, or irreversible and permanent. It has been recognized since the 19th century. [1] There are many well-known ototoxic drugs used in clinical situations, and they are prescribed, despite the risk of hearing disorders, for very serious health conditions. [2] Ototoxic drugs include antibiotics (such as gentamicin, streptomycin, tobramycin), loop diuretics (such as furosemide), and platinum-based chemotherapy agents (such as cisplatin and carboplatin). A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. [3] [4] This can result in sensorineural hearing loss, dysequilibrium, or both. Some environmental and occupational chemicals have also been shown to affect the auditory system and interact with noise. [5]
Ototoxicity results in cochlear and/or vestibular dysfunction which can manifest as sensorineural hearing loss, tinnitus, hyperacusis, dizziness, vertigo, or imbalance. [6] [7] Presentation of symptoms vary in singularity, onset, severity and reversibility. [6]
The cochlea is primarily a hearing structure situated in the inner ear. It is the snail-shaped shell containing several nerve endings that makes hearing possible. [8] Ototoxicity typically results when the inner ear is poisoned by medication that damages the cochlea, vestibule, semicircular canals, or the auditory/ vestibulocochlear nerve. The damaged structure then produces the symptoms the patient presents with. Ototoxicity in the cochlea may cause hearing loss of the high-frequency pitch ranges or complete deafness, or losses at points between. [9] It may present with bilaterally symmetrical symptoms, or asymmetrically, with one ear developing the condition after the other or not at all. [9] The time frames for progress of the disease vary greatly and symptoms of hearing loss may be temporary or permanent. [8]
The vestibule and semicircular canal s are inner-ear components that comprise the vestibular system. Together they detect all directions of head movement. Two types of otolith organs are housed in the vestibule: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs together sense the head's position with respect to gravity when the body is static; then the head's movement when it tilts; and pitch changes during any linear motion of the head. The saccule and utricle detect different motions, which information the brain receives and integrates to determine where the head is and how and where it is moving.
The semicircular canals are three bony structures filled with fluid. As with the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented at right angles to the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis. When a medication is toxic in the vestibule or the semicircular canals, the patient senses loss of balance or orientation rather than losses in hearing. Symptoms in these organs present as vertigo, difficulties walking in low light and darkness, disequilibrium, oscillopsia among others. [9] Each of these problems is related to balance and the mind is confused with the direction of motion or lack of motion. Both the vestibule and semicircular canals transmit information to the brain about movement; when these are poisoned, they are unable to function properly which results in miscommunication with the brain.
When the vestibule and/or semicircular canals are affected by ototoxicity, the eye can also be affected. Nystagmus and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and "woozy" feeling patients use to describe conditions such as oscillopsia and vertigo. [9]
Cranial nerve VIII is the least affected component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficulty walking, deafness, and balance and orientation issues.
Ototoxicity-induced hearing loss typically impacts the high frequency range, affecting above 8000 Hz prior to impacting frequencies below. [10] There is not global consensus on measuring severity of ototoxicity-induced hearing loss as there are many criteria available to define and measure ototoxicity-induced hearing loss. [11] [12] Guidelines and criteria differ between children and adults. [10]
There are at least 13 classifications for ototoxicity. [13] Examples of ototoxicity grades for hearing loss are the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), Brock's Hearing Loss Grades, Tune grading system, and Chang grading system [11] .
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009) [10] :
Brock's Hearing Loss Grades (as described in the American Academy of Audiology Ototoxicity Monitoring Guidelines from 2009) [10] :
Chang grading system (as reported in Ganesan et al., 2018) [11] :
Tune grading system (as reported in Ganesan et al., 2018) [11] :
Hyperacusis is abnormally increased sensitivity to intensity (perceived as loudness) to what is typically deemed as normal/tolerable loudness.
Vestibular symptoms from ototoxicity, which would specifically be vestibulotoxicity, can include general dizziness, vertigo, imbalance, and oscillopsia.
Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism. [14] It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. [15] Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. [16] Once-daily dosing [17] and co-administration of N-acetylcysteine [18] may protect against aminoglycoside-induced ototoxicity. The anti-bacterial activity of aminoglycoside compounds is due to inhibition of ribosome function and these compounds similarly inhibit protein synthesis by mitochondrial ribosomes because mitochondria evolved from a bacterial ancestor. [19] Consequently, aminoglycoside effects on production of reactive oxygen species as well as dysregulation of cellular calcium ion homeostasis may result from disruption of mitochondrial function. [20] Ototoxicity of gentamicin can be exploited to treat some individuals with Ménière's disease by destroying the inner ear, which stops the vertigo attacks but causes permanent deafness. [21] Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.
Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. [22] The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis. [22] Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation. [22]
Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. [23] The related compound ethacrynic acid has a higher association with ototoxicity, and is therefore used only in patients with sulfa allergies. Diuretics are thought to alter the ionic gradient within the stria vascularis. [24] Bumetanide confers a decreased risk of ototoxicity compared to furosemide. [22]
Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by progressive, high-frequency hearing loss with or without tinnitus (ringing in the ears). [25] Ototoxicity is less frequently seen with the related compound oxaliplatin. [26] The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered [27] and the age of the patient, with young children being most susceptible. [28] The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outer hair cells, as well as damage to the spiral ganglion neurons and cells of the stria vascularis. [29] Long-term retention of cisplatin in the cochlea may contribute to the drug's cochleotoxic potential. [30] Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production of reactive oxygen species. [31] The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. [26] Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use. [32]
The vinca alkaloids, [33] [34] [35] including vincristine, [36] are also associated with reversible ototoxicity. [22]
Topical skin preparations such as chlorhexidine and ethyl alcohol have the potential to be ototoxic should they enter the inner ear through the round window membrane. [22] This potential was first noted after a small percentage of patients undergoing early myringoplasty operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine. [37] The ototoxicity of chlorhexidine was further confirmed by studies with animal models. [22]
Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations include acetic acid, propylene glycol, quaternary ammonium compounds, and any alcohol-based preparations. However, it is difficult to extrapolate these results to human ototoxicity because the human round window membrane is much thicker than in any animal model. [22]
At high doses, quinine, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug. [22] Erectile dysfunction medications may have the potential to cause hearing loss. [38] However the link between erectile dysfunction medications and hearing loss remains uncertain. [39]
Previous noise exposure has not been found to potentiate ototoxic hearing loss. [40] [41] The American Academy of Audiology includes in their position statement that exposure to noise at the same time as aminoglycosides may exacerbate ototoxicity. The American Academy of Audiology recommends people being treated with ototoxic chemotherapeutics avoid excessive noise levels during treatment and for several months following cessation of treatment. Opiates in combination with excessive noise levels may also have an additive effect on ototoxic hearing loss. [42]
Ototoxic effects are also seen with quinine, pesticides, solvents, asphyxiants, and heavy metals such as mercury and lead. [5] [22] [43] [44] When combining multiple ototoxicants, the risk of hearing loss becomes greater. [45] [46] As these exposures are common, this hearing impairment can affect many occupations and industries. [47] [48] Examples of activities that often have exposures to both noise and solvents include: [49]
Ototoxic chemicals in the environment (from contaminated air or water) or in the workplace interact with mechanical stresses on the hair cells of the cochlea in different ways. For mixtures containing organic solvents such as toluene, styrene or xylene, the combined exposure with noise increases the risk of occupational hearing loss in a synergistic manner. [5] [50] The risk is greatest when the co-exposure is with impulse noise. [51] [52] Carbon monoxide has been shown to increase the severity of the hearing loss from noise. [50] Given the potential for enhanced risk of hearing loss, exposures and contact with products such as fuels, paint thinners, degreasers, white spirits, exhaust, should be kept to a minimum. [53] Noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by regulatory agencies.
Drug exposures mixed with noise potentially lead to increased risk of ototoxic hearing loss. Noise exposure combined with the chemotherapeutic cisplatin puts individuals at increased risk of ototoxic hearing loss. [40] Noise at 85 dB SPL or above added to the amount of hair cell death in the high frequency region of the cochlea in chinchillas. [54]
The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise. A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information. [55]
No specific treatment may be available, but withdrawal of the ototoxic drug may be warranted when the consequences of doing so are less severe than those of the ototoxicity. [22] Co-administration of anti-oxidants may limit the ototoxic effects. [40]
Ototoxic monitoring during exposure is recommended by the American Academy of Audiology to allow for proper detection and possible prevention or rehabilitation of the hearing loss through a cochlear implant or hearing aid. Monitoring can be completed through performing otoacoustic emissions testing or high frequency audiometry. Successful monitoring includes a baseline test before, or soon after, exposure to the ototoxicant. Follow-up testing is completed in increments after the first exposure, throughout the cessation of treatment. Shifts in hearing status are monitored and relayed to the prescribing physician to make treatment decisions. [56]
It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Diagnosis of ototoxicity typically results from ruling out all other possible sources of hearing loss and is often the catchall explanation for the symptoms. Treatment options vary depending on the patient and the diagnosis. Some patients experience only temporary symptoms that do not require drastic treatment while others can be treated with medication. Physical therapy may prove useful for regaining balance and walking abilities. Cochlear implants are sometimes an option to restore hearing. Such treatments are typically taken to comfort the patient, not to cure the disease or damage caused by ototoxicity. There is no cure or restoration capability if the damage becomes permanent, [57] [58] although cochlear nerve terminal regeneration has been observed in chickens, [59] which suggests that there may be a way to accomplish this in humans.
Several guidelines have been published around the world, though there is not consensus on one universally agreed-upon protocol [12] [13] . Guidelines released:
Auditory testing involved in ototoxicity monitoring/management (OtoM) is typically general audiological evaluation, high frequency audiometry (HFA), and otoacoustic emissions (OAEs) [61] [60] . High frequency audiometry evaluates hearing thresholds beyond 8000 Hz, which is the typical cut-off for conventional audiometry. [61] It is recommended a baseline evaluation be performed prior to treatment beginning. [61] [60]
There are several guidelines on what constitutes a significant change in hearing [61] [63] which can indicate further action must be taken, whether that be to implement aural rehabilitation or adjust the source of ototoxic exposure (eg. chemotherapy). With pure tone audiometry, ASHA considers a significant change to have occurred if there is a [64] [60] :
If using distortion product ototoacoustic emissions (DPOAEs), a significant shift is observed if there is a reduction in amplitude by 6 dB or more than the baseline within the sensitive range of ototoxicity. [64]
Vestibular tests for vestibulotoxicity specifically can include caloric testing, rotational testing, vestibular evoked myogenic potentials (VEMPs), and computerized dynamic posturography (CDP); however, there are no globally accepted guidelines for monitoring/management of vestibular function during or following ototoxic treatments. [61]
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken language, and in adults it can create difficulties with social interaction and at work. Hearing loss can be temporary or permanent. Hearing loss related to age usually affects both ears and is due to cochlear hair cell loss. In some people, particularly older people, hearing loss can result in loneliness.
The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus. A core component of the cochlea is the organ of Corti, the sensory organ of hearing, which is distributed along the partition separating the fluid chambers in the coiled tapered tube of the cochlea.
The vestibulocochlear nerve or auditory vestibular nerve, also known as the eighth cranial nerve, cranial nerve VIII, or simply CN VIII, is a cranial nerve that transmits sound and equilibrium (balance) information from the inner ear to the brain. Through olivocochlear fibers, it also transmits motor and modulatory information from the superior olivary complex in the brainstem to the cochlea.
The organ of Corti, or spiral organ, is the receptor organ for hearing and is located in the mammalian cochlea. This highly varied strip of epithelial cells allows for transduction of auditory signals into nerve impulses' action potential. Transduction occurs through vibrations of structures in the inner ear causing displacement of cochlear fluid and movement of hair cells at the organ of Corti to produce electrochemical signals.
The acoustic reflex is an involuntary muscle contraction that occurs in the middle ear in response to loud sound stimuli or when the person starts to vocalize.
Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear, sensory organ, or the vestibulocochlear nerve. SNHL accounts for about 90% of reported hearing loss. SNHL is usually permanent and can be mild, moderate, severe, profound, or total. Various other descriptors can be used depending on the shape of the audiogram, such as high frequency, low frequency, U-shaped, notched, peaked, or flat.
An otoacoustic emission (OAE) is a sound that is generated from within the inner ear. Having been predicted by Austrian astrophysicist Thomas Gold in 1948, its existence was first demonstrated experimentally by British physicist David Kemp in 1978, and otoacoustic emissions have since been shown to arise through a number of different cellular and mechanical causes within the inner ear. Studies have shown that OAEs disappear after the inner ear has been damaged, so OAEs are often used in the laboratory and the clinic as a measure of inner ear health.
Audiometry is a branch of audiology and the science of measuring hearing acuity for variations in sound intensity and pitch and for tonal purity, involving thresholds and differing frequencies. Typically, audiometric tests determine a subject's hearing levels with the help of an audiometer, but may also measure ability to discriminate between different sound intensities, recognize pitch, or distinguish speech from background noise. Acoustic reflex and otoacoustic emissions may also be measured. Results of audiometric tests are used to diagnose hearing loss or diseases of the ear, and often make use of an audiogram.
Presbycusis, or age-related hearing loss, is the cumulative effect of aging on hearing. It is a progressive and irreversible bilateral symmetrical age-related sensorineural hearing loss resulting from degeneration of the cochlea or associated structures of the inner ear or auditory nerves. The hearing loss is most marked at higher frequencies. Hearing loss that accumulates with age but is caused by factors other than normal aging is not presbycusis, although differentiating the individual effects of distinct causes of hearing loss can be difficult.
An audiogram is a graph that shows the audible threshold for standardized frequencies as measured by an audiometer. The Y axis represents intensity measured in decibels (dB) and the X axis represents frequency measured in hertz (Hz). The threshold of hearing is plotted relative to a standardised curve that represents 'normal' hearing, in dB(HL). They are not the same as equal-loudness contours, which are a set of curves representing equal loudness at different levels, as well as at the threshold of hearing, in absolute terms measured in dB SPL.
The auditory brainstem response (ABR), also called brainstem evoked response audiometry (BERA) or brainstem auditory evoked potentials (BAEPs) or brainstem auditory evoked responses (BAERs) is an auditory evoked potential extracted from ongoing electrical activity in the brain and recorded via electrodes placed on the scalp. The measured recording is a series of six to seven vertex positive waves of which I through V are evaluated. These waves, labeled with Roman numerals in Jewett and Williston convention, occur in the first 10 milliseconds after onset of an auditory stimulus. The ABR is considered an exogenous response because it is dependent upon external factors.
Noise-induced hearing loss (NIHL) is a hearing impairment resulting from exposure to loud sound. People may have a loss of perception of a narrow range of frequencies or impaired perception of sound including sensitivity to sound or ringing in the ears. When exposure to hazards such as noise occur at work and is associated with hearing loss, it is referred to as occupational hearing loss.
Pure-tone audiometry is the main hearing test used to identify hearing threshold levels of an individual, enabling determination of the degree, type and configuration of a hearing loss and thus providing a basis for diagnosis and management. Pure-tone audiometry is a subjective, behavioural measurement of a hearing threshold, as it relies on patient responses to pure tone stimuli. Therefore, pure-tone audiometry is only used on adults and children old enough to cooperate with the test procedure. As with most clinical tests, standardized calibration of the test environment, the equipment and the stimuli is needed before testing proceeds. Pure-tone audiometry only measures audibility thresholds, rather than other aspects of hearing such as sound localization and speech recognition. However, there are benefits to using pure-tone audiometry over other forms of hearing test, such as click auditory brainstem response (ABR). Pure-tone audiometry provides ear specific thresholds, and uses frequency specific pure tones to give place specific responses, so that the configuration of a hearing loss can be identified. As pure-tone audiometry uses both air and bone conduction audiometry, the type of loss can also be identified via the air-bone gap. Although pure-tone audiometry has many clinical benefits, it is not perfect at identifying all losses, such as ‘dead regions’ of the cochlea and neuropathies such as auditory processing disorder (APD). This raises the question of whether or not audiograms accurately predict someone's perceived degree of disability.
Hearing, or auditory perception, is the ability to perceive sounds through an organ, such as an ear, by detecting vibrations as periodic changes in the pressure of a surrounding medium. The academic field concerned with hearing is auditory science.
Auditory fatigue is defined as a temporary loss of hearing after exposure to sound. This results in a temporary shift of the auditory threshold known as a temporary threshold shift (TTS). The damage can become permanent if sufficient recovery time is not allowed before continued sound exposure. When the hearing loss is rooted from a traumatic occurrence, it may be classified as noise-induced hearing loss, or NIHL.
Occupational hearing loss (OHL) is hearing loss that occurs as a result of occupational hazards, such as excessive noise and ototoxic chemicals. Noise is a common workplace hazard, and recognized as the risk factor for noise-induced hearing loss and tinnitus but it is not the only risk factor that can result in a work-related hearing loss. Also, noise-induced hearing loss can result from exposures that are not restricted to the occupational setting.
Acoustic trauma is the sustainment of an injury to the eardrum as a result of a very loud noise. Its scope usually covers loud noises with a short duration, such as an explosion, gunshot or a burst of loud shouting. Quieter sounds that are concentrated in a narrow frequency may also cause damage to specific frequency receptors. The range of severity can vary from pain to hearing loss.
Sharon G. Kujawa is a clinical audiologist, Director of Audiology Research at the Massachusetts Eye and Ear Infirmary, Associate Professor of Otology and Laryngology at Harvard Medical School, and Adjunct Faculty of Harvard-MIT Health Sciences and Technology.and specialist in otolaryngology, Her specialty is the effects of noise exposure and aging on auditory function.
Causes of hearing loss include ageing, genetics, perinatal problems, loud sounds, and diseases. For some kinds of hearing loss the cause may be classified as of unknown cause.
Ototoxicity is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent hearing loss (cochleotoxic) and balancing problems (vestibulotoxic). Drugs or pharmaceutical agents inducing ototoxicity are regarded as ototoxic medications.
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