Ototoxic Hearing Loss

Cochlear, vestibular or combined injury caused by therapeutic or environmental agents. It is characteristically bilateral, symmetrical, dose related and begins at the highest frequencies, progressing basal to apical.

Mechanisms by drug class

Aminoglycosides: taken up by hair cells through the mechanotransduction channel and the megalin receptor, they generate reactive oxygen species and trigger apoptosis of outer hair cells in the basal turn. Injury is delayed, continuing for weeks after the last dose, so a normal audiogram at the end of a course does not exclude damage. Gentamicin, tobramycin and streptomycin are predominantly vestibulotoxic; amikacin, kanamycin and neomycin are predominantly cochleotoxic.
Platinum agents: cisplatin accumulates in the stria vascularis and outer hair cells, causing irreversible loss. Incidence of significant loss exceeds 50 percent, and approaches 60 percent in children. Carboplatin is substantially less toxic at standard doses, oxaliplatin least.
Loop diuretics: furosemide, bumetanide and ethacrynic acid inhibit the sodium potassium chloride cotransporter in the stria vascularis, reducing the endocochlear potential. The effect is usually reversible, but is potentiated severely when combined with aminoglycosides and is worse with rapid intravenous injection and in renal failure.
Salicylates: reversible tinnitus and a flat loss of 20 to 40 dB at high serum levels through cochlear prostaglandin and outer hair cell prestin effects. Resolves within 72 hours of cessation.
Quinine and chloroquine: tinnitus and reversible high frequency loss, occasionally permanent with prolonged exposure.
Macrolides: erythromycin and azithromycin cause reversible loss at high intravenous doses, especially in renal or hepatic impairment.
Vancomycin: ototoxicity is modest alone but real in combination with aminoglycosides.
Antimalarials, deferoxamine, vinca alkaloids and topical aminoglycoside and antiseptic preparations entering a perforated ear.
Environmental: toluene, styrene, xylene, carbon disulfide, lead and carbon monoxide, all of which act synergistically with noise. Solvent exposed workers exposed to noise sustain greater loss than either exposure predicts.

Genetic susceptibility

The mitochondrial 12S ribosomal RNA m.1555A>G variant causes profound aminoglycoside induced deafness after a single conventional dose. It is maternally inherited. A maternal family history of deafness after antibiotics should prevent aminoglycoside use where any alternative exists, and rapid genotyping is available in some settings.

Risk factors: cumulative dose and duration, renal impairment, prior or concurrent noise exposure, dehydration, age extremes, prior ototoxic exposure, and concurrent use of two ototoxic classes.

Tinnitus, high pitched, frequently the first symptom and a warning sign that should trigger reassessment of the drug.
Bilateral symmetrical high frequency sensorineural loss, initially above 8000 Hz and therefore undetectable on conventional audiometry until it is already extensive.
Progression into the speech frequencies with difficulty understanding conversation.
Vestibulotoxicity presents differently from cochleotoxicity and is frequently missed: oscillopsia with bouncing vision when walking or driving, unsteadiness in the dark and on uneven ground, and a wide based gait, without vertigo, because bilateral simultaneous loss produces no asymmetry to generate spinning.
Onset may be during treatment or weeks afterwards.

Examination

Normal otoscopy.
Bilaterally positive head impulse test in vestibulotoxicity.
Positive dynamic visual acuity test, with a drop of three or more lines on the Snellen chart during head oscillation.
Positive Romberg, worse with eyes closed, and inability to perform tandem gait.

Baseline audiometry before starting any ototoxic regimen, including extended high frequency testing to 16000 Hz where available.
Serial monitoring: weekly during aminoglycoside therapy, before each cisplatin cycle, and at 1, 3 and 6 months after completion given the delayed onset.
Significant shift is conventionally a decrease of 20 dB at any one frequency, 10 dB at two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously present.
Otoacoustic emissions detect outer hair cell dysfunction before threshold change and are practical in children and in the unwell.
Auditory brainstem response for infants and unresponsive patients.
Vestibular testing where vestibulotoxicity is suspected: video head impulse testing showing bilaterally reduced gain, caloric testing showing bilateral hypofunction, and rotational chair testing, which is the most sensitive for bilateral loss.
Therapeutic drug monitoring with trough and peak levels, and renal function.
Consider mitochondrial genetic testing where deafness follows a single or short aminoglycoside course, or with a maternal family history.

No treatment reverses established ototoxic injury. Everything of value happens before and during exposure.

Prevention, which is the substance of management

Use ototoxic agents only where indicated, for the shortest effective duration, and choose less toxic alternatives where equally effective.
Once daily aminoglycoside dosing reduces cochlear uptake compared with divided dosing while maintaining efficacy, since uptake is saturable.
Therapeutic drug monitoring with trough levels, adjusting dose interval rather than dose in renal impairment. Gentamicin trough should generally be below 1 mg/L on once daily dosing.
Maintain hydration and avoid concurrent nephrotoxins.
Avoid combining aminoglycosides with loop diuretics or vancomycin unless unavoidable, and monitor intensively when combined.
Administer intravenous furosemide slowly, no faster than 4 mg per minute, in renal impairment.
Take a maternal family history before prescribing aminoglycosides.
Never prescribe aminoglycoside containing ear drops for a perforated tympanic membrane or an open mastoid cavity where a quinolone is available.
Avoid noise exposure during and for months after platinum and aminoglycoside therapy, since the effects are synergistic.

Monitoring protocol during treatment

Baseline audiogram, then serial testing as above, with a documented plan for what will be done if a shift occurs.
Any threshold shift or new tinnitus prompts an urgent discussion with the treating team about substitution, dose reduction or acceptance of risk, which is a decision balancing the infection or malignancy against permanent deafness.
Where an aminoglycoside is being used for a life threatening infection such as multidrug resistant tuberculosis, hearing loss may be an accepted cost, but that decision must be explicit and documented rather than accidental.

Otoprotection

Sodium thiosulfate given 6 hours after cisplatin infusion reduces hearing loss in children with localised hepatoblastoma without compromising tumour control, and is used in selected paediatric oncology protocols. Timing matters, since earlier administration reduces chemotherapy efficacy.
N acetylcysteine, amifostine and antioxidants have inconsistent evidence and are not routine.
Intratympanic dexamethasone and sodium thiosulfate have been explored for cisplatin protection with variable results.

Rehabilitation of established loss

Hearing aids for aidable loss, with attention to the steeply sloping configuration.
Cochlear implantation for severe to profound loss, which performs well in this group since the auditory nerve is typically preserved.
Vestibular rehabilitation for bilateral vestibulopathy, focusing on substitution with vision and proprioception rather than adaptation, since there is no residual function to adapt.
Counsel on falls prevention, avoidance of night driving, use of a light when moving at night, caution with swimming where loss of orientation underwater is dangerous, and occupational implications for those working at height or driving.
Formal falls assessment and home hazard modification.
Tinnitus management.

Follow up

Audiometry at 1, 3, 6 and 12 months after exposure, then annually where loss has occurred. Document the exposure clearly in the record and flag the patient as at risk from future ototoxic prescribing.

Clinical toolsCalculators

BMI GCS EDD Parkland Formula

Corrected Sodium Corrected Calcium Anion Gap Creatinine Clearance Insulin Calculations qSOFA Wells PE Wells DVT CHA₂DS₂-VASc HAS-BLED CURB-65 Centor/McIsaac

Ramsay Hunt Syndrome

Also known as: Herpes zoster oticus

Herpes zoster oticus with peripheral facial nerve palsy, caused by reactivation of varicella zoster virus latent in the geniculate ganglion. It accounts for around 12 percent of facial palsies and carries a substantially worse prognosis than Bell palsy.

Pathophysiology

Reactivated virus produces ganglionitis, neuritis and inflammatory oedema within the fallopian canal, which is a rigid bony channel with the narrowest segment at the labyrinthine portion and the meatal foramen, roughly 0.68 mm in diameter. Swelling here produces compression, ischaemia and Wallerian degeneration. Because the virus produces direct neuronal destruction rather than the predominantly oedematous injury of Bell palsy, axonal loss is greater and recovery poorer.

Spread to adjacent cranial nerves is common. The vestibulocochlear nerve is involved in up to 40 percent through the internal auditory canal, and cranial nerves V, IX, X and XI may be affected, producing polycranial neuropathy.

Prognosis

Complete recovery of facial function occurs in around 75 percent of Bell palsy but only 20 to 50 percent of Ramsay Hunt syndrome.
Treatment within 72 hours substantially improves outcome, with recovery rates of around 75 percent when treated within 3 days falling to around 30 percent when treated after 7 days.
Complete palsy at presentation, age over 50 years, diabetes, hypertension and associated vertigo or hearing loss all predict poorer recovery.

Risk factors: age over 60, immunosuppression, HIV, malignancy, diabetes, and physiological or psychological stress. Ramsay Hunt syndrome in a young adult should prompt HIV testing.

The classical triad is ipsilateral facial palsy, ear pain, and a vesicular rash in the ear or mouth, but the components frequently appear sequentially over several days, and the rash may follow the palsy, which causes delayed diagnosis.

Severe deep otalgia, often preceding the rash by 1 to 3 days and disproportionate to physical findings. Severe pain preceding facial palsy should raise the diagnosis before any rash appears.
Vesicular eruption on the concha, external auditory canal, tympanic membrane, or on the anterior two thirds of the tongue and soft palate. Distribution follows the sensory territory of the nervus intermedius and the auricular branch of the vagus.
Lower motor neurone facial palsy involving the forehead, with inability to close the eye, loss of the nasolabial fold, and drooping of the mouth. Progression from partial to complete palsy over 3 to 5 days is typical.
Sensorineural hearing loss and tinnitus in up to 40 percent.
Vertigo, nausea and vomiting in a similar proportion.
Dysgeusia and reduced lacrimation, reflecting involvement above the chorda tympani and greater petrosal nerve respectively.
Hyperacusis from stapedius paralysis.

Zoster sine herpete: facial palsy with severe pain and audiovestibular symptoms but no rash, which is confirmed serologically or by polymerase chain reaction and which is a recognised and frequently missed variant. Treat as Ramsay Hunt syndrome when the clinical picture fits, since waiting for a rash wastes the treatment window.

Assessment of the palsy

Grade with the House Brackmann scale, from I normal to VI complete paralysis, and document at each review.
Test each branch: frontal, orbital, zygomatic, buccal, mandibular and cervical.
Assess the eye specifically: ability to close, Bell phenomenon, corneal sensation and any existing corneal staining.
A partial palsy that is progressing requires the same urgency as a complete one.

Red flags

Bilateral facial palsy, which suggests Lyme disease, Guillain Barré syndrome, sarcoidosis or HIV seroconversion.
Slowly progressive palsy over weeks, which suggests a tumour of the parotid, temporal bone or cerebellopontine angle rather than an inflammatory cause.
Facial twitching or spasm preceding the palsy, which suggests a neoplasm.
Associated other cranial neuropathies, meningism or altered consciousness, which suggest meningoencephalitis or vasculitis.
No recovery at 4 months, which mandates imaging.

The diagnosis is clinical, and treatment must not await confirmation.

Examine the entire external ear, canal, drum, palate and tongue under good light and magnification for vesicles, which are easily missed in the canal.
House Brackmann grading and photographic documentation.
Pure tone audiometry in all patients, since hearing loss is frequent and influences prognosis.
Vestibular assessment where vertigo is present.
Polymerase chain reaction for varicella zoster virus DNA from vesicle fluid, saliva, or tears, which is the most useful confirmatory test and is positive in zoster sine herpete.
Paired varicella zoster virus serology showing a fourfold rise, useful retrospectively.
Blood glucose, HbA1c and HIV testing in all patients.
Lyme serology where there is a relevant exposure history or bilateral palsy.
Electroneuronography between days 3 and 14 in complete palsy, comparing the compound muscle action potential amplitude with the normal side. Degeneration exceeding 90 percent within 14 days indicates a poor prognosis and is used in some centres to select patients for surgical decompression.
Electromyography for evidence of voluntary motor unit potentials, which indicates preserved axons and a better outlook.
Magnetic resonance imaging with gadolinium where the palsy is atypical, progressive beyond 3 weeks, bilateral, associated with other cranial neuropathies, or not recovering by 4 months. It shows enhancement of the labyrinthine and geniculate segments, and excludes tumour and stroke.

Differential diagnosis

Bell palsy: no rash, less pain, better prognosis. Ramsay Hunt is distinguished by the severity of pain and by audiovestibular involvement even before a rash appears.
Lyme disease: erythema migrans, tick exposure, frequently bilateral.
Acute or chronic otitis media with facial palsy: otoscopic findings of middle ear disease.
Malignant otitis externa in a diabetic: granulation at the bony cartilaginous junction, raised erythrocyte sedimentation rate.
Parotid malignancy: a mass, slowly progressive palsy.
Cerebellopontine angle tumour: gradual onset, other cranial nerve signs.
Stroke: upper motor neurone pattern with forehead sparing, and other neurological deficits.

Treat immediately on clinical suspicion. Every day of delay costs recovery.

Antiviral therapy, started within 72 hours

Aciclovir 800 mg orally five times daily for 7 to 10 days.
Valaciclovir 1 g orally three times daily for 7 days, which has better bioavailability and simpler dosing and is preferred where available.
Famciclovir 500 mg orally three times daily for 7 days.
Intravenous aciclovir 10 mg/kg every 8 hours for severe disease, immunocompromise, or central nervous system involvement.
Renal dose adjustment is required and is frequently overlooked. Reduce dosing interval in creatinine clearance below 50 mL/min, and ensure adequate hydration to prevent crystal nephropathy.
Children: aciclovir 20 mg/kg orally four times daily, maximum 800 mg per dose.
Antivirals started beyond 72 hours are still given, since benefit persists while new vesicles are forming, but efficacy declines.

Corticosteroids, given concurrently

Prednisolone 1 mg/kg orally daily, maximum 60 to 80 mg, for 5 to 7 days followed by a taper over a further 5 to 7 days.
Combination antiviral plus corticosteroid is superior to either alone in this condition, in contrast to Bell palsy where the steroid carries most of the benefit.
Monitor glucose in diabetics with a plan for insulin adjustment, add gastroprotection where indicated, and counsel on mood and sleep disturbance.

Eye care, which prevents the most serious avoidable complication

Corneal exposure keratopathy causing ulceration and permanent visual loss is the principal preventable harm, and eye care is more often neglected than the antivirals.
Ocular lubricant drops such as hypromellose or carbomer hourly during the day.
Lubricating ointment at night with taping of the eyelid closed, or a moisture chamber.
Protective glasses outdoors.
Ophthalmology referral for any pain, redness, visual disturbance or corneal staining.
Consider a temporary tarsorrhaphy, botulinum toxin induced ptosis or an upper eyelid weight where the palsy is complete, corneal sensation is reduced, or the Bell phenomenon is absent, since these patients are at highest risk.

Analgesia and neuropathic pain

Paracetamol 1 g every 6 hours and a nonsteroidal anti inflammatory drug where not contraindicated.
Opioids for severe acute pain.
Neuropathic agents for the zoster pain and for postherpetic neuralgia: amitriptyline 10 to 25 mg at night titrated to 75 mg; gabapentin 300 mg at night titrated to 1200 to 3600 mg daily in divided doses; or pregabalin 75 mg twice daily titrated to 300 to 600 mg daily. Reduce all of these in renal impairment and in the elderly.
Postherpetic neuralgia occurs in a significant minority and requires ongoing management.

Vertigo and hearing loss

Vestibular sedatives for no more than 48 to 72 hours, then vestibular rehabilitation.
Sensorineural hearing loss is treated with the same corticosteroid regimen already in use; intratympanic steroid may be added for severe loss.
Repeat audiometry at 4 to 6 weeks and 3 months.

Facial nerve decompression

Remains controversial and is performed in few centres. It is considered for complete palsy with greater than 90 percent degeneration on electroneuronography within 14 days of onset, using a middle fossa approach to decompress the labyrinthine segment and meatal foramen.
Evidence of benefit is weak, the procedure carries risks of hearing loss and cerebrospinal fluid leak, and it is not standard care.

Rehabilitation of incomplete recovery

Facial neuromuscular retraining with a specialist physiotherapist, begun once some voluntary movement returns. Avoid gross exercises and electrical stimulation, which promote synkinesis.
Botulinum toxin for synkinesis and for hyperkinesis of the contralateral side, which improves symmetry.
Surgical rehabilitation for permanent palsy: static slings, gold or platinum upper eyelid weight, lower lid tightening, and dynamic reanimation with nerve transfer or free muscle transfer in appropriate candidates.
Psychological support, since facial disfigurement carries substantial social and emotional consequences that are routinely underestimated.

Prevention

Herpes zoster vaccination with the recombinant adjuvanted vaccine in adults aged 50 and over, and in immunocompromised adults from age 18, reduces zoster incidence and postherpetic neuralgia substantially and is the only effective preventive measure.

Ototoxic Hearing Loss

Overview

Clinical Features

Diagnosis

Management

Overview

Clinical Features

Diagnosis

Management