Cisplatin Differentially Damages Mammalian Vestibular End Organs

Objectives: Cisplatin is an effective anticancer drug that can induce cochleotoxicity in up to 50 to 60% of treated patients. However, the vestibulotoxic potential of cisplatin remains unclear. Our lab previously developed a multicycle model of cisplatin administration in mice that results in hearing loss similar to that observed clinically. The purpose of this study was to comprehensively characterize the functional and morphological consequences of cisplatin on the vestibular periphery in this mouse model. Design: Twenty-nine adult CBA/CaJ mice were assigned to control or cisplatin-treated groups. Cisplatin-treated mice received three consecutive cycles of once-daily cisplatin for 4 days followed by a 10-day recovery period. Mice underwent vestibular sensory evoked potential testing before cisplatin administration, after the final cycle of cisplatin, and 6 mo after treatment cessation. Mice also underwent vestibulo-ocular reflex testing and vestibular afferent single-unit recordings 6 mo after treatment cessation. Following testing, utricles, saccules, and horizontal semicircular canals were microdissected, and vestibular morphology was examined. To examine whether our data in mice were consistent with reports of cisplatin-induced vestibulotoxicity in patients, histopathology reports of human temporal bones were examined for evidence of cisplatin-induced vestibulotoxicity. Results: Vestibular sensory evoked potential thresholds were significantly elevated in cisplatin-treated mice immediately after cessation of cisplatin administration and progressively worsened 6 mo later. Rotational and translational vestibulo-ocular reflexes were generally unaffected by cisplatin. Cisplatin did not cause statistically significant changes in the spontaneous firing rates of semicircular canal afferents but did cause significant decreases in their overall regularity. No statistically significant differences in the spontaneous firing rates or regularity of otolith afferents were observed. However, cisplatin-treated mice exhibited statistically significant decreases in the percentage of low-distortion otolith afferents, indicating that responses of these afferents to head translations were more variable and less precise. Cisplatin-treated mice showed significantly decreased hair cell numbers in the saccule but not in the utricle or horizontal semicircular canal. One temporal bone histopathology report from an individual treated with high cumulative cisplatin was consistent with the results of our study, showing only saccular degeneration with normal utricle and semicircular canal morphology. Conclusions: Our study demonstrates cisplatin’s potential to affect the vestibular end organs adversely and differentially. The saccule was uniquely susceptible in our mouse model, suggesting that it may be possible to screen for cisplatin-induced vestibulotoxicity by testing saccular function. While very little is known about the potential for progression of cisplatin-induced vestibulotoxicity, our results suggest vestibular dysfunction may continue to worsen after cessation of cisplatin treatment. We recommend that ongoing and future efforts at evaluating vestibular function in patients treated with cisplatin include monitoring and evaluation of otolith function.