Acquired Causes of Hearing Loss: Ototoxicity, ANSD, and Temporal Bone Trauma

Definition and Scope of Ototoxicity

Ototoxicity refers to the tendency of certain therapeutic agents to cause functional impairment and cellular degeneration within the structures of the inner ear and the eighth cranial nerve ($CN\,VIII$). These agents are frequently identified as chemical teratogens. The resulting damage may manifest as neurotoxicity, where the site of action is central to the eighth cranial nerve, or as inner ear dysfunction. Specifically, inner ear dysfunction is categorized as cochleotoxic if it results in hearing loss, vestibulotoxic if it results in dizziness or balance issues, or a combination of both. The physiological damage caused by these drugs can be either temporary or permanent, leading to reversible or irreversible hearing loss. Generally, drug-induced hearing loss presents as a rapidly progressive sensorineural hearing loss ($SNHL$) that is bilateral in nature.

Aminoglycosides and Mechanisms of Toxicity

Aminoglycosides are a class of antibiotics known for their potent ototoxic effects. They are further divided based on whether they primarily target the cochlear or vestibular systems. Cochleotoxic aminoglycosides include dihydrostreptomycin, kanamycin, neomycin, amikacin, tobramycin, and netilmicin. Vestibulotoxic aminoglycosides include streptomycin and gentamicin. In terms of otopathology, the outer hair cells ($OHC$) of the basal turn are typically the first to be damaged, with the degeneration potentially spreading to more apical regions of the cochlea over time. Specifically, the inner row of outer hair cells is affected before the other two rows of $OHCs$. Inner hair cells ($IHC$) are generally more resistant to aminoglycoside-induced injury than outer hair cells.

There are two primary mechanisms of toxicity for aminoglycosides. First, they compete with calcium for entry into the $OHC$ through mechano-electrical transduction ($MET$) channels, where they act as permanent blockers. Second, the drugs react with inner ear tissues to form an active, ototoxic metabolite consisting of reactive oxygen species ($ROS$). This formation triggers apoptosis and necrotic cell death. Toxicity generally only occurs after days or weeks of exposure, but because of these active metabolites, delayed ototoxicity may occur $1$ to $3$ weeks after the cessation of therapy. The onset is unpredictable and may not correlate with the cumulative dose. High-frequency bilateral hearing loss usually occurs first and may be detectable before becoming clinically noticeable. Continued exposure leads to progression into lower frequencies, including the speech range ($250$ to $4000\,Hz$). A diagnosis of drug-related hearing loss is confirmed when there is a documented hearing loss of $20\,dB$ or more at two or more adjacent frequencies, following the exclusion of other causes.

Risk Factors for Aminoglycoside Ototoxicity

The risk of developing aminoglycoside-induced hearing loss is influenced by several clinical and genetic factors. Clinical risk factors include therapy lasting longer than $7$ days, elevated serum levels of the drug, prior exposure to aminoglycosides, and high daily doses. Patient demographics such as age (specifically neonates and children) play a role, as do medical conditions like bacteremia, fever, hepatic dysfunction, and renal dysfunction. Environmental and pre-existing factors include pre-existing hearing loss and noise exposure. Furthermore, undergoing simultaneous treatment with multiple ototoxic drugs increases risk. Genetically, mutations in the mitochondrial $12S$ ribosomal $RNA$ significantly influence susceptibility to aminoglycoside ototoxicity.

Cisplatin and Antineoplastic Ototoxicity

Cisplatin is a potent anti-neoplastic agent used in the treatment of malignant tumors. The risk of cisplatin-induced ototoxicity is related to the dose administered, the patient's age, noise exposure, exposure to other ototoxic drugs, depleted nutritional state, low serum albumin, anemia, and cranial irradiation. Genetic susceptibility is influenced by gene polymorphisms of megalin, a low-density lipoprotein expressed in marginal cells. The otopathology of cisplatin involves the degeneration of the $OHC$ (with the first row affected initially) in the lower turns of the cochlea, the spiral ganglia, and the cochlear nerve. Observations include a decreased number of both $IHC$ and $OHC$ and spiral ganglion cells, along with an atrophic stria vascularis and stereocilia abnormalities, such as fusion.

Diuretics and Stria Vascularis Impact

Diuretics are potent synthetic drugs that exert therapeutic effects through action on the loop of Henle, leading to a rapid and dramatic increase in urine output. Examples include Furosemide, bumetanide, and ethacrynic acid. These loop diuretics work by inhibiting the re-absorption of sodium, potassium, and chloride ions by blocking the $Na-K-2Cl$ carrier. Hearing loss associated with Furosemide is typically linked to plasma levels greater than $50\,mg/L$. The sensorineural hearing loss may be accompanied by symptoms of tinnitus and vertigo. The primary target inside the stria vascularis is the $Na-2Cl-K$ transporter ($SLC12A2$). Damage to the stria vascularis results in extensive edema, a reduction of the endocochlear potential ($EP$), and an elevation of the compound action potential ($CAP$) threshold.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Salicylates

Salicylates and $NSAIDs$ are used to treat mild to moderate pain due to their anti-inflammatory and analgesic effects. Hearing loss from these drugs is directly related to the concentration of salicylates in the blood, exhibiting a linear relationship between hearing loss and free salicylate concentrations. Site of lesion testing typically indicates a cochlear site of lesion. Tinnitus tends to increase when plasma concentrations of salicylate reach $40$ to $320\,mg/dL$. Notably, histopathologic studies do not show significant hair cell damage or injury to the stria vascularis, spiral ganglion cells, or the myelin sheath of $CN\,VIII$. Instead, salicylates cause a reversible $SNHL$ by altering the function of the motor protein, Prestin, within the outer hair cells.

Quinine and Macrolides

Quinine is an alkaloid drug used for treating malaria and leg cramps, and it is also found in tonic drinks. Excessive consumption or treatment can lead to cinchonism, characterized by deafness, vertigo, tinnitus, headache, visual loss, and nausea. Quinine causes high-frequency hearing loss and poor speech discrimination scores with prolonged treatment. While the loss may be reversible, if it occurs within the speech frequencies, the damage may become permanent. Macrolides, such as Erythromycin, cause dose-related and reversible hearing loss. The audiometric pattern is usually a flat type $SNHL$, though some patients manifest high-frequency loss. During therapy, Auditory Brainstem Response ($ABR$) testing may show an absence of waves $I$ to $III$ even while pure-tone audiograms document $SNHL$. Both the $ABR$ pattern and audiograms typically normalize after therapy cessation.

Auditory Neuropathy Spectrum Disorder (ANSD)

Auditory Neuropathy Spectrum Disorder ($ANSD$) is a distinct hearing disorder characterized by the presence of normal hair cell function alongside abnormal neural conduction. Specifically, a diagnosis requires three criteria: evidence of poor auditory function in at least some settings, poor auditory neural function as evidenced by abnormal or absent $ABR$, and normal hair cell function as evidenced by normal otoacoustic emissions ($OAE$) or cochlear microphonics ($CM$). It has a prevalence of $11\%$ among children with hearing loss and $0.23\%$ within the at-risk population. Approximately $27\%$ of patients have an associated peripheral neuropathy, such as Charcot-Marie-Tooth disease or Friedreich ataxia. Genetic factors include autosomal dominant inheritance associated with peripheral neuropathies (genes $MPZ$, $PMP22$, $GJB1$, and $EGR2$) or autosomal recessive non-syndromic inheritance via the $OTOF$ mutation. Risk factors include hyperbilirubinemia, perinatal asphyxia, prematurity, ototoxicity, mechanical ventilation, family history, and consanguinity; however, $25$ to $35\%$ of cases have no known risk factors.

Clinical and Pathologic Features of ANSD

Clinical features of $ANSD$ include an inconsistent response to sound, speech understanding that is significantly poorer than what is predicted by the audiogram, and very poor speech understanding in background noise. Patients often find it difficult to learn spoken language through listening alone. Audiological findings typically include absent or severely abnormal $ABR$ with present $CM$ and often present $OAE$. Behavioral thresholds can range from normal to profound and may fluctuate. Acoustic reflexes, both ipsilateral and contralateral, are absent. Speech recognition in quiet ranges from normal to profoundly impaired, but speech discrimination in noise is usually very poor. There is also an absence of contralateral $OAE$ suppression. The pathologic lesion can affect the inner hair cells, the synapse between the $IHC$ and the spiral ganglion cell, or the afferent fibers of the eighth nerve (which is the most common site). It may involve a myelin disorder or axonal neuropathy, resulting in dyssynchrony among auditory nerve fibers or reduced neural input.

Temporal Bone Trauma Classification and Statistics

Temporal bone trauma occurs in $14$ to $22\%$ of all skull injuries, with a male-to-female ratio of $3:1$. These injuries are bilateral in $9$ to $20\%$ of cases, and children account for $8$ to $22\%$ of the patient population. Producing a temporal bone fracture requires an average force of $1875\,lbs$ at a speed of $25\,mph$. Traditionally, fractures are divided based on the axis of the petrous ridge. Longitudinal fractures ($70$ to $90\%$ of cases) result from temporoparietal impact and run parallel to the long axis of the petrous pyramid, with facial nerve injury occurring in $10$ to $25\%$. Transverse fractures ($10$ to $30\%$ of cases) result from fronto-occipital impact and run perpendicular to the long axis, with facial nerve injury occurring in $30$ to $50\%$. Clinical features across types include otorrhea (bloody with or without $CSF$), hemotympanum, tympanic membrane perforation, facial palsy, Raccoon sign (periorbital ecchymosis), and Battle’s Sign (post-auricular ecchymosis).

Otic Capsule Involvement in Fractures

A new classification scheme categorizes fractures based on whether the otic capsule is involved. Otic Capsule Sparing Fractures ($OCSF$) represent $94.2$ to $97.5\%$ of cases and are caused by blows to the temporoparietal region. They typically result in conductive or mixed hearing loss, hemotympanum, and ossicular chain dislocation in $20\%$ of cases. Facial nerve paralysis occurs in $6$ to $14\%$ of $OCSF$ cases, and a $CSF$ leak is less likely. Otic Capsule Disrupting Fractures ($OCDF$) represent $2.5$ to $5.8\%$ of cases and are caused by blows to the occipital region. They result in sensorineural hearing loss due to disruption of the membranous labyrinth, avulsion or trauma to the cochlear nerve, interruption of cochlear blood supply, hemorrhage into the cochlea, perilymphatic fistulas, or obstruction of the endolymphatic duct. Facial nerve paralysis is much more common in $OCDF$ ($30$ to $50\%$), and a $CSF$ leak is $2$ to $4$ times more likely than in $OCSF$.