Ototoxicity

Ototoxicity is damage to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, by a toxin. It is commonly medication-induced; ototoxic drugs include antibiotics such as the aminoglycoside gentamicin, loop diuretics such as furosemide, and platinum-based chemotherapy agents such as cisplatin. A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. This can result in sensorineural hearing loss, dysequilibrium, or both. Either may be reversible and temporary, or irreversible and permanent.

Antibiotics
Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism. It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. Once-daily dosing and co-administration of N-acetylcysteine may protect against aminoglycoside-induced ototoxicity. The 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.

Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis. Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.

Loop diuretics
The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. The related compound ethacrynic acid has a higher association with ototoxicity, therefore it is only preferred in patients with sulfur allergies. Bumetanide confers a decreased risk of ototoxicity compared to furosemide.

Chemotherapeutic agents
Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by high-frequency hearing loss and tinnitus (ringing in the ears). Ototoxicity is less frequently seen with the related compound oxaliplatin. Cisplatin-induced ototoxicity is dose-dependent, typically occurring with doses greater than 60 mg/m2, and tend to occur when chemotherapy is given every two weeks compared to every one week. Cisplatin and related agents are absorbed by the cochlear hair cells and result in ototoxicity through the production of reactive oxygen species. The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. 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.

The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity.

Others
Ototoxic effects are also seen with quinine and heavy metals such as mercury and lead. At high doses, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug. The erectile dysfunction medications Viagra, Levitra, and Cialis have also been reported to cause hearing loss.

Mixed Exposures
Ototoxic chemicals interact with mechanical stresses on the hair cells of the cochlea in different ways. For organic solvents such as Toluene, styrene or xylene, the combined exposure with noise increases the risk of hearing loss in a synergistic manner Heavy metals, asphyxiants and endocrine disruptors have a variety of interactions as well. Specific toxicity limits for combined exposures are not well established. However, given the potential for enhanced risk of hearing loss, the noise exposures should be kept below 85 decibels and the chemical exposures should be below the recommended exposure limits given by agencies such as OSHA, NIOSH, or ACGIH.

Symptoms
Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus.

Ototoxicity is the result of the inner ear being poisoned by a medication which subsequently causes damage to the cochlea, vestibule, semi-circular canals, or auditory/ vestibulocochlear nerve. The structure afflicted with Ototoxicity also affects the symptoms the patient presents with. The cochlea is primarily a hearing structure. Within the inner ear, it is the snail shaped shell that contains several nerve endings and makes hearing possible. When a patient develops ototoxicity in the cochlea, they experience hearing loss that can range from loss of the high frequency pitch ranges to complete deafness. Ototoxicity most commonly presents itself with bilaterally symmetrical symptoms, but if the symptoms do present asymmetrically, it is possible the other ear will develop the condition at a later time. The time frame in which the patient experiences hearing loss remains debatable as the symptoms which patients suffer vary greatly. In many instances, symptoms are temporary; however, there are many cases in which the hearing loss is permanent. The cochlea can also develop tinnitus from ototoxicity, causing a ringing sound in the ears which only the patient can hear.

The vestibule and semi-circular canal are inner-ear components which comprise the vestibular system, another area of the ear affected by ototoxicity. Due to the difference in the function of these structures, ototoxic poisoning affects the patient differently than in the case of cochlear damage. The vestibule is where the two types of otolith organs are housed: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs detect the head’s position with respect to gravity when the body is static, the head’s movement in an angular or tilted direction, and pitch changes during any linear motion of the head. The saccule and utricle work together to detect different motions that the brain later integrates to correctly determine exactly where the head is and how and where it is moving.

The vestibule and the semi-circular canals work together to detect all forms of head movement. The semi-circular canals are three bony structures that are filled with fluid. Just as the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented independently at right angles from 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 causes an ototoxic reaction in either the vestibule or semi-circular canals, the patient suffers from problems in balance and orientation rather than hearing issues. Symptoms in these organs present as vertigo, difficulties walking at night, and disequilibrium, oscillopsia among other balance related problems. Each of these problems is directly related to balance and the mind being confused with the direction of motion or lack of motion. Because both the vestibule and semi-circular 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 semi-circular 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.

The auditory/vestibulocochlear nerve, or cranial nerve VIII, is the least afflicted component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Cranial nerve VIII “has a vestibular part which functions in balance, equilibrium, and orientation in three-dimensional space, and a cochlear part which functions in hearing." Despite the vestibular or cochlear structures functioning normally, affliction of the nerve effectively arrests communication between these structures and the brain. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficultly walking, deafness, and balance and orientation issues.

Treatment
No specific treatment is available, but immediate withdrawal of the drug may be warranted in cases where the consequences of doing so are less severe than the consequences of the ototoxicity.

It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms. Often ototoxicity diagnoses result from ruling out all other possible sources of hearing loss and is the catchall explanation for the sudden problem. Treatment options vary depending on the patient and the diagnosis. Some patients only experience temporary symptoms, which do not require drastic treatment while other patients can be treated with medication. Physical therapy remains particularly useful with regaining balance and walking abilities. Cochlear implants are sometimes an option as well to restore hearing. However, these treatments are more often made in an effort to make the patient as comfortable as possible and to help them cope with the symptoms, not to cure them of the disease or damage caused by ototoxicity. There is no cure or restoration capability if the damage becomes permanent.