Physiology of the ear
The ear is a sensory organ that detects sound, head position and movement. The outer ear collects sound waves and directs them to the tympanic membrane that, along with the middle ear ossicular chain, amplifies sound vibration and transforms it into fluid shifts within the inner ear. The organ of Corti in the cochlea contains sensory receptor hair cells, which are set into motion by vibration of the cochlear duct basement membrane. Hair cell motion displaces the hair cell stereocilia projecting from the cell apex. This results in cellular depolarization produced by an inward cation current (calcium ion (Ca2 + ), sodium ion (Na + )) entering the apical end of the hair cell. The hair cell then releases a chemical transmitter from its basal end, leading to stimulation of the afferent bipolar neurons of the auditory nerve that connects to the central nervous system (CNS). Stereocilial deflection in the opposite direction results in hair cell hyperpolarization, which inhibits basal neurotransmitter release and suppresses auditory neurons, activity. Stereocilial oscillation therefore produces a train of excitatory and inhibitory impulses within the auditory nerve with the same frequency characteristics as the original sound. Balance depends on inputs from the vestibular, visual and proprioceptive sensory systems to the balance centres of the brain. The peripheral vestibular systems to the balance consist of the following:
The otolithic organs, the utricle and saccule, which sense linear acceleration
The semicircular canals, which sense angular acceleration or rotation
The sensory input from these organs is critical for maintaining equilibrium and stabilizing gaze with head movement. Depending on head position or movement, vestibular hair cells are either depolarized or hyperpolarized. Depolarization increases the basal release of neurotransmitter and the resting firing rate of the associated vestibular afferent neuron. Hyperpolarization has the opposite effect. Head movement and position are therefore resolved into stimulatory increases or inhibitory decreases of the resting firing rate of the vestibular nerve and its central connection.
Diseases of the ear
The main symptoms of ear disorders are hearing loss, tinnitus, vertigo, pain, pressure and itchiness.
Hearing loss may be conductive (resulting from disorders of external or middle ear sound conduction) or sensorineural (resulting from abnormalities of the inner ear sensory cells and their connections with the CNS). Drugs which induce hearing loss as an adverse effect usually affect the sensorineural pathway.
Ear infections are extremely common and involve the outer ear (otitis externa), middle ear (otitis media) or inner ear (labyrinthitis).
Otitis externa results from a bacterial or fungal infection of the soft tissue of the external ear canal. Common bacterial causes include Pseudomonas aeruginosa , Proteus mirabilis , staphylococci, streptococci and various Gram-negative bacteria. Candida and Aspergillus species are the most common fungal causes. Most pathogens are inhibited by an acidic medium, and a solution of equal parts of vinegar and isopropyl alcohol can be used to treat otitis externa. All infected debris and pus must be removed from the ear (otic toilet) before starting any medication. Moisture should be avoided. First-line treatment of otitis externa includes the use of topical preparations combining an appropriate antibiotic (e.g. neomycin and polymyxin) and a glucocorticoid (e.g. hydrocortisone). Topically applied polysorbate, gentian violet or nystatin may be used to treat fungal infections. Orally administered dicloxacillin, cephalexin, trimethoprim-sulfamethoxazole or ciprofloxacin are used to treat progressive cellulitis of the external ear canal, while intravenous cefazolin, dicloxacillin or ciprofloxacin may be needed for more severe cases. For the treatment of invasive skull base osteitis, combination therapy is required, preferably aztreonam with clindamycin or a combination of ciprofloxacin with one of the following antibiotics: ticarcillin, piperacillin, ceftazidime, imipenem, gentamicin, tobramycin or amikacin.
Acute purulent otitis media is caused by a bacterial infection of the middle ear. The usual pathogens are Streptococcus pneumoniae , Haemophilus influenza , and Moraxella catarrhalis . First-line therapy should include amoxicillin or erythromycin plus a sulphonamide or trimethoprim-sulfamethoxazole. Second-line therapy is directed at ß lactamase-producing organisms and is usually amoxicillin-clavulanate, cefaclor, cefuroxime, cefixime or clarithromycin.
Use of nasal spray containing a corticosteroid to promote drainage by opening the eustachian tubes can also be useful.
Chronic otitis media is defined by the presence of a perforated tympanic membrane in the presence of a middle ear infection caused by the presence of P. aeruginosa , Proteus spp. staphylococci, Gram-negative organisms, and/or anaerobes ( Klebsiella spp., Escherichia coli , Bacteroides fragilis ). Treatment includes use of ear drops containing neomycin and polymyxin and an oral antibiotic such as trimethoprim-sulfamethoxazole or cephalexin, though amoxicillin-clavulanate or ciprofloxacin with metronidazole is sometimes used. If pseudomonas is the cause of persistent otorrhea, combining two different ear drops, one containing ciprofloxacin and the other an aminoglycoside (gentamicin, tobramycin), may be effective. However, aminoglycosides can cause ototoxicity when applied to the middle ear, but this is rare in the presence of active infection.
Bacterial infection of the spaces of the inner ear causes profound cochlear and vestibular destruction and loss of both hearing and vestibular function in the affected ear. Intralabyrinthine infection results from the spread of otitis media via the round or oval windows, a labyrinthine fistula or a lateral extension of meningitis through the cochlear aqueduct and cribriform plate at the lateral end of the internal auditory canal.
If infection is due to otitis media, treatment includes surgical drainage and intravenous antibiotics (ceftriaxone for acute otitis media, nafcillin with ceftazidime plus metronidazole for chronic otitis media). If infection is due to meningitis, the appropriate intravenous antibiotic should be given.
Certain ototoxic drugs are common, e.g. aminoglycosides and certain macrolides.
Otosclerosis is characterized by idiopathic circumscribed endochondral otic capsule bone destruction and replacement with vascular bone and then dense lamellar bone in the anterior oval window niche, which results in stapes footplate fixation and a conductive hearing loss. Sensorineural hearing loss can result from a focus of otosclerosis adjacent to the endolymphatic space. Epidemiologic studies indicate a lower incidence of otosclerosis in regions with high fluoride concentrations in drinking water. However, the only widely recognized indication for using fluoride is progressive sensorineural hearing loss with a high risk of otosclerosis on taking the patient’s history or upon examination. Calcium, 2–3 g daily, should be administered along with the fluoride.
Sudden sensorineural hearing loss
Sudden sensorineural hearing loss (SSHL) is usually unilateral, progresses within hours to days and is associated with tinnitus and, less frequently, vertigo. It can be caused by a viral infection, vascular disorder or inner ear membrane rupture. SSHL is a medical emergency and is usually treated by glucocorticoids tapered over 10 days to 2 weeks.
Autoimmune hearing loss
Autoimmune sensorineural hearing loss typically affects young adults, is slowly progressive over months and is not accompanied by other systemic disease or hereditary defects, but it is due to an autoimmune reaction to a specific inner ear antigen. There is no vertigo, but more severe disease causes ataxia in dim light. For more severe and bilateral cases, prednisone for 2–4 weeks is the treatment of choice. A second immunosuppressive agent may be needed if there is a good response and hearing recovers, but the patient becomes chronically dependent on glucocorticoids. Cyclophosphamide, methotrexate, or penicillamine are the drugs of choice.
Tinnitus is the perception of sound in the absence of an external source. It may be objective and result from sounds generated within the body which are audible to an observer, or subjective and characterized by an auditory sensation in the absence of a physical sound.
Causes include musculoskeletal and vascular sounds producing objective tinnitus, and disorders of the peripheral and central auditory systems, which usually produce subjective tinnitus. The cause may be known (e.g. noise-induced, presbycusis). The first symptom of drug-induced ototoxicity is often tinnitus. Nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and some antineoplastic agents can cause tinnitus. Most patients also have an irreversible high-frequency sensorineural hearing loss. Once an underlying disease has been excluded, the goal is to relieve the annoyance that tinnitus causes. If it is mild, patients may simply need to know its cause and that it is benign. Masking (the use of a noise generator to cover the subjective sound) is the prime treatment for more severe cases, although drugs may be needed to treat intractable tinnitus including local anaesthetics (procaine, lidocaine), benzodiazepines (diazepam, alprazolam, clonazepam) or γ-aminobutyric acid (GABA) agonists such as baclofen or tricyclic antidepressants (amitriptyline).
The treatment of tinnitus with local anaesthetics probably involves inhibition of the cochlear nerve and its brainstem connections. Lidocaine must be given intravenously and can produce a highly significant reduction in tinnitus. Benzodiazepines improve the patient’s emotional response to tinnitus, but in some patients this may be a direct effect as the tinnitus may be due to insufficient inhibitory activity in the ascending auditory system. Benzodiazepines may act by enhancing the activity of the inhibitory neurotransmitter, GABA.
Vertigo, vestibular neuronitis and vestibular trauma
Vertigo is the hallucinatory perception of movement and can result from disorders of the peripheral or central vestibular systems. Peripherally induced vertigo is usually the more severe and associated with other aural symptoms such as hearing loss or tinnitus. Vertigo is produced by benign positional vertigo, which is either spontaneous or secondary to head trauma, occurs with motion of the head and usually lasts less than 30 seconds. There is a sensation of rotary motion, either of the world moving or one moving in the world. Malpositioning of otoliths is presumed to trigger an attack. It is treated by systematic head maneuvers and positioning to try to re-position the otoliths of the inner ear. Vertigo can also be caused by constant, often permanent, hypofunction of the affected labyrinth, for example acute vestibular neuronitis, suppurative labyrinthitis, and vestibular trauma. Transient fluctuations in vestibular neuron activity such as Ménière’s disease and recurrent vestibulopathy can also lead to vertigo.
Vestibular neuronitis results in an acute decrease in vestibular function, which may be mild and reversible or profound and permanent. Symptoms include severe vertigo which can be accompanied by nausea and is probably caused by an unknown virus. Vestibular trauma can have a similar range of severity, depending upon whether there has been a brain concussion, total destruction of the vestibular structures or division of the vestibular nerve. Central adaptation must begin during the first month after onset. Patients must remain active, as forced inactivity may predispose to incomplete adaptation and permanent ataxia. Drugs such as dimenhydrinate are used to treat severe nausea, and the vestibular suppressants used for acute Ménière’s disease (see below) can be used sparingly. No medication specifically promotes central adaptation.
Ménière’s disease and recurrent vestibulopathy
Meniere’s disease is a peripheral vestibular disorder associated with intermittent overaccumulation of endolymphatic fluid (endolymphatic hydrops). It causes episodes of severe rotary vertigo that continue for hours, hearing loss, tinnitus and a pressure sensation in the ear. Initially these symptoms occur in attacks, but eventually the condition burns out, leaving the patient with a stable severe sensorineural hearing loss and a permanent, usually well-compensated, decrease in peripheral vestibular function. Ménière’s disease is managed with drugs, diets to restrict Na + intake and prevent hydrops and physical therapy to adapt to the loss of vestibular function. Drugs used to treat Ménière’s disease include diuretics (e.g. hydrochlorothiazide, furosemide) to limit endolymphatic fluid accumulation, vestibular suppressants (sedatives, H 1 receptor antagonists, muscarinic receptor antagonists and narcotics) and vasodilating drugs or aminoglycosides to ablate peripheral vestibular function.
Hydrochlorothiazide prevents recurrent vertigo in many patients, but patients must be monitored for potassium (K + ) depletion by repeated measurements of serum K + and maintain a high potassium diet. Meclizine is useful to treat moderate acute attacks and it is likely that this occurs via its capacity to antagonize muscarinic receptors rather than H 1 histamine receptors. This is an example of a drug known to be in one class (H 1 receptor antagonism) which actually has its therapeutic benefit through another mechanism common to a different class of compounds (muscarinic receptor antagonists). If an attack becomes severe, a benzodiazepine such as diazepam or lorazepam not only provides sedation, but also acts directly on the medial and lateral vestibular nuclei to suppress otolithic and semicircular canal activity. Muscarinic receptor antagonists such as scopolamine have limited use because their adverse effects are more profound than those of meclizine. Some parenteral narcotics (e.g. fentanyl, droperidol) are potent vestibular suppressants and are occasionally needed for the treatment of an acute, incapacitating attack. Chemical ablation of vestibular function may be indicated for recurrent incapacitating vertigo that cannot be controlled by drugs; the patient with physician guidance must decide if it would be easier to cope with a permanent, medically induced loss of vestibular function. Streptomycin can be given parenterally for active disease in both ears and is carefully titrated to a point of symptom control, but all peripheral vestibular function must not be ablated as this can cause incapacitating oscillopsia and ataxia. For unilateral Ménière’s disease, gentamicin can be injected directly into the middle ear, from where it is actively transported across the round window into the labyrinthine fluids. Here it probably acts on dark cells (thought to be important in the production of endolymph) and has a toxic effect on the vestibular hair cells. Most patients adapt well after unilateral destruction of vestibular function and have no further disabling spells of vertigo. Recurrent vestibulopathy, also known as vestibular Ménière’s disease, presents with similar recurrent vertigo but with no auditory symptoms. The vertigo is typically more benign than that of Ménière’s disease and is usually controlled with similar drugs.
Facial nerve palsy
Bell’s palsy is acute unilateral facial weakness or paralysis without an identifiable cause, though herpes simplex virus type I has been implicated in this condition. Herpes zoster oticus (HZO) is acute facial paralysis with pain and varicelliform lesions, which often involves the conchal bowl, the concave central portion of the external ear. It is probably due to varicella-zoster virus infection of the geniculate ganglion and there is often eighth cranial nerve involvement, producing a profound sensorineural hearing loss and vestibular loss. Oedema traps the facial nerve as it passes through the narrow fallopian canal, resulting in ischemia and neural dysfunction. The use of glucocorticoids to treat acute facial paralysis is controversial and they are not indicated for incomplete facial paralysis, as this usually recovers fully without the need for treatment. When glucocorticoids are used for the treatment of complete facial paralysis due to Bell’s palsy or HZO, they should be given within the first 10 days at a moderate dose, which is then tapered. Acyclovir (acycloguanosine), a nucleoside analogue that inhibits viral DNA replication, reduces functional deficits in immunocompromised patients with HZO but has no proven benefit in the treatment of Bell’s palsy. Ideally treatment should be started as soon as possible after symptoms develop, up to about 72 hours after onset.
Travel or motion sickness can be treated with older H 1 receptor antagonists such as hyoscine.
Four clinically important classes of drugs can cause inner ear toxicity affecting both hearing and balance. Tinnitus is an additional symptom that often accompanies drug-induced ototoxicity.
Analgesics and antipyretics
The tinnitus characteristic of salicylate-induced ototoxicity is often accompanied by hearing loss, but the mechanism of salicylate ototoxicity is not fully understood. However, salicylates accumulate within extracellular fluid compartments and reduce prostaglandin synthesis within the stria vascularis by inhibiting cyclooxygenase which causes vasoconstriction within the stria vascularis, ischemia and inhibition of the cochlear nerve action potential. Salicylate ototoxicity occurs at serum concentrations over 0.35 mg/mL and is reversible within 48–72 hours of salicylate withdrawal.
Aminoglycoside antibiotics have adverse effects on the kidney and inner ear: streptomycin and gentamicin are more vestibulotoxic; kanamycin, tobramycin and amikacin have more effect on cochlear hair cells. Gentamicin-induced ototoxicity occurs in approximately 5% of patients treated with this drug. Netilmicin has a reported prevalence of hearing loss in 1 per 250 patients and vestibular toxicity in 1 per 150 patients. Aminoglycosides first bind to the outer surface of the hair cell membrane and disturb Ca2 + membrane channels. They then bind to phosphatidylinositol bisphosphate on the inner surface of the cell membrane. Interference with intracellular Ca2 + and polyamine-regulated processes causes additional membrane damage, which eventually leads to cell death by apoptosis. Reversible ototoxicity can occur; however, severe, irreversible and untreatable hearing deficits are common. As patients requiring aminoglycosides often have debilitating medical conditions, early complaints of dizziness and tinnitus may be overlooked, especially in a bed-bound patient. Permanent disabling vestibulotoxicity often is only recognized when the mobile patient complains of movement intolerance, oscillopsia (difficulty in stabilizing gaze during head movement) and/or ataxia.
Glycopeptide antibiotics such as vancomycin are increasingly used clinically on account of increasing incidence of resistance to certain bacteria. Their mechanism of ototoxicity is not clear, but the pattern with outer hair cell loss preceding inner hair cell loss is similar to that seen with aminoglycosides, likely due to apoptosis. High-frequency sensorineural hearing loss, blowing tinnitus and vertigo can also follow large intravenous doses of erythromycin, a macrolide antibiotic. Although the mechanism of this ototoxicity is unknown, it is reversible on drug withdrawal.
Cisplatin’s ototoxic effect is probably due to local production of oxidants such as nitric oxide (NO) and induction of apoptosis with resulting labyrinthine hair cell degeneration. Cisplatin is primarily cochleotoxic, causing degeneration of the outer hair cells, spiral ganglion cells and cochlear neurons, with relative sparing of the vestibular system. The morphologic changes within the inner ear are similar to those of aminoglycoside ototoxicity. The outer hair cells of the basal turn of the cochlea are the most susceptible. Carboplatin also produces dose-dependent hearing loss, thought to result from generation of oxidative free radicals and subsequent apoptosis of cochlear cells.
Loop diuretics (furosemide and ethacrynic acid) inhibit chloride ion (Cl – ) reabsorption at the distal loop of Henle and promote extra cellular fluid excretion. Within the inner ear they inhibit cell membrane K + transport within the stria vascularis and are principally cochleotoxic. Like aminoglycosides, loop diuretics have adverse effects on both the kidney and inner ear, and the toxic effects of these two medications can be synergistic. There is an increased risk of toxicity if the drug is given too rapidly by bolus injection, or if the patient is elderly or has renal failure. Tinnitus, hearing loss and vertigo may occur within minutes and can be reversible if the medication is withdrawn immediately.