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  • Updated 05.20.2024
  • Released 05.09.2023
  • Expires For CME 05.20.2027

Ototoxicity

Introduction

Overview

With the widespread use of streptomycin in the late 1940s, clinicians began to recognize the full clinical syndrome of acquired bilateral vestibulopathy. Some patients treated with streptomycin for tuberculosis developed severe ataxia and oscillopsia. The clinical features of patients with streptomycin ototoxicity resembled those described earlier in patients with Meniere disease following surgical section of both vestibular nerves to alleviate vertigo. It is now recognized that ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both. Various drugs are ototoxic, including aminoglycosides, aspirin, furosemide, and platinum-based alkylating agents used in cancer chemotherapy. Aminoglycosides are by far the most commonly implicated agents in permanent drug-induced vestibulotoxicity. Aspirin and loop diuretics typically cause reversible cochleotoxicity, and alkylating agents uncommonly cause a mixed ototoxicity. Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow. In addition, vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes. Damage is usually complete by 6 months after aminoglycoside discontinuation. Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function. Aminoglycoside therapy should cease as soon as symptoms of either auditory or vestibular ototoxicity appear to avoid permanent impairment.

Key points

• Ototoxicity can present as cochleotoxicity, vestibulotoxicity, or both.

• Cochleotoxicity typically presents with subacute or chronic high-frequency hearing loss and subjective tinnitus.

• Patients with vestibulotoxicity typically present with features of subacute bilateral vestibulopathy, with gait ataxia and oscillopsia.

• Following vestibulotoxic insults (eg, from aminoglycosides), the hair cells do not regrow.

• Vestibular damage may progress for months after the responsible drug is discontinued because the drugs are bound to inner ear membranes.

• Damage is usually complete by 6 months after aminoglycoside discontinuation.

• Compensation for bilateral vestibulopathy is often achieved by augmentation of visual and proprioceptive reflexes rather than by recovery of vestibular function.

• Risk factors for aminoglycoside-induced ototoxicity include family history of ototoxicity, high serum levels, higher total dose, longer duration of therapy (beyond 7 to 10 days), intrathecal administration, previous exposure to ototoxins, concomitant use of other nephrotoxic or ototoxic drugs (eg, vancomycin, loop diuretics, cis-platinum, metronidazole), renal impairment, fever, and older age.

• Prevention of aminoglycoside-induced vestibulotoxicity is essential because the hair cells do not regrow after vestibulotoxic insults; hence, vestibular function does not recover. Instead, the limited compensation that occurs after bilateral vestibulopathy is generally achieved by augmentation of visual and proprioceptive reflexes.

• Corrective saccades after rapid head turns to either side (ie, the “head thrust test”) can be helpful in the diagnosis of bilateral vestibular dysfunction.

Historical note and terminology

With the widespread use of streptomycin in the late 1940s, clinicians began to recognize the full clinical syndrome of acquired bilateral vestibulopathy. Some patients treated with streptomycin for tuberculosis developed severe ataxia and oscillopsia (64).

The clinical features of patients with streptomycin ototoxicity resembled those described earlier in 1936 by neurologist Frank Rodolph Ford (1892–1970) and neuro-ophthalmologist Frank Burton Walsh (1895–1978) of Johns Hopkins in a patient of neurosurgeon Walter Dandy’s (1886–1946) (38; 27; 79). In their original report, Ford and Walsh stated: “During convalescence [following bilateral vestibular nerve section] it became evident that a new series of symptoms had developed. Objects seemed to move before his eyes unless his head was kept perfectly still. Walking caused objects to ‘jump’ before his eyes to some extent. . . He was also very unsteady in the dark.” Dandy had not reported these observations in his original report on this patient, although the postoperative period was brief at the time of Dandy’s report (28).

In 1941, 5 years after the report by Ford and Walsh, Dandy described oscillopsia and imbalance in the dark in patients with Meniere disease in whom he had sectioned both vestibular nerves to alleviate vertigo (27):

“Division of both vestibular nerves is attended by one rather surprising after effect, jumbling of objects (visual) when the patient is in motion. As soon as the patient is at rest, the objects are again perfectly clear. The other disturbance is uncertainty when the patient is walking in the dark. Both of these effects persist, though with gradual lessening in severity.”

Because of a historical misunderstanding of Dandy's role in recognizing the clinical features of bilateral vestibulopathy, the syndrome of bilateral vestibulopathy is sometimes mislabeled “Dandy syndrome” (79).

Ford later summarized the observations he made with Walsh in the 1930s (37):

“Destruction of the vestibular apparatus on both sides in man produces a constant unsteadiness of station and gait which is exaggerated in the dark and also by sudden movements of the head. There is also a striking inability to fix objects with the eyes when the head is in movement so that the patients complain of objects seeming to dance or oscillate before their eyes when they are walking or riding in a car. This oscillation ceases as soon as the head is held still.”

The classic description of aminoglycoside vestibulotoxicity by "JC" (John Crawford MD). In 1948, shortly after streptomycin became available, a 30-year-old physician was treated with intramuscular and intraarticular streptomycin for presumptive tuberculous arthritis of the knee (64; 82). After 2.5 months of treatment, the patient noted the dramatic onset and rapid progression of bilateral vestibular dysfunction over several days. Manifestations included postural instability in darkness (Romberg symptom), gait ataxia, motion-induced vertigo and nausea, and oscillopsia.

Oscillopsia was initially severe. Even the cardioballistic effects of the pulse produced disturbing perceptions of motion. He was able to read by bracing his head between two metal bars on the bed and keeping his place with a finger or a pencil. He had to stand still to read the lettering on signs or to recognize familiar faces.

To ambulate, he initially had to rely on tactile cues and hold on to objects for support. Later, he was able to walk by focusing on distant objects. After 4 years, he had learned to walk fairly well in the light and had resumed most of his former recreational activities, despite continued vestibular dysfunction. One partial benefit was a recognized resistance to seasickness. However, he was still severely impaired in the dark and sometimes had to move about on his hands and knees.

Forty years later he was still active with little disability. He noted continued resistance to motion sickness. He continued to have difficulty on uneven or unstable surfaces and in the dark.

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