Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation

Abstract

Bilateral vestibular deficiency (BVD) due to gentamicin ototoxicity can significantly impact quality of life and result in large socioeconomic burdens. Restoring sensation of head rotation using an implantable multichannel vestibular prosthesis (MVP) is a promising treatment approach that has been tested in animals and humans. However, uncertainty remains regarding the histopathologic effects of gentamicin ototoxicity alone or in combination with electrode implantation. Understanding these histological changes is important because selective MVP-driven stimulation of semicircular canals (SCCs) depends on persistence of primary afferent innervation in each SCC crista despite both the primary cause of BVD (e.g., ototoxic injury) and surgical trauma associated with MVP implantation. Retraction of primary afferents out of the cristae and back toward Scarpa's ganglion would render spatially selective stimulation difficult to achieve and could limit utility of an MVP that relies on electrodes implanted in the lumen of each ampulla. We investigated histopathologic changes of the inner ear associated with intratympanic gentamicin (ITG) injection and/or MVP electrode array implantation in 11 temporal bones from six rhesus macaque monkeys. Hematoxylin and eosin-stained 10-μm temporal bone sections were examined under light microscopy for four treatment groups: normal (three ears), ITG-only (two ears), MVP-only (two ears), and ITG + MVP (four ears). We estimated vestibular hair cell (HC) surface densities for each sensory neuroepithelium and compared findings across end organs and treatment groups. In ITG-only, MVP-only, and ITG + MVP ears, we observed decreased but persistent ampullary nerve fibers of SCC cristae despite ITG treatment and/or MVP electrode implantation. ITG-only and ITG + MVP ears exhibited neuroepithelial thinning and loss of type I HCs in the cristae but little effect on the maculae. MVP-only and ITG + MVP ears exhibited no signs of trauma to the cochlea or otolith end organs except in a single case of saccular injury due to over-insertion of the posterior SCC electrode. While implanted electrodes reached to within 50-760 μm of the target cristae and were usually ensheathed in a thin fibrotic capsule, dense fibrotic reaction and osteoneogenesis were each observed in only one of six electrode tracts examined. Consistent with physiologic studies that have demonstrated directionally appropriate vestibulo-ocular reflex responses to MVP electrical stimulation years after implantation in these animals, histologic findings in t h e p r e s e n t s t u d y i n d i c a t e t h a t a l t h o u g h intralabyrinthine MVP implantation causes some inner

Continuous vestibular implant stimulation partially restores eye-stabilizing reflexes

“…Although failure of vestibular reflexes can be caused by downstream lesions in the central nervous system, it often results from hair cell injury, dysfunction, or death caused by ototoxic injury (e.g., by gentamicin and other aminoglycoside antibiotics), ischemia, infection, Ménière's disease, or genetic inner ear abnormalities (11). For many such cases, the insult spares primary vestibular afferent neurons (12). When vestibular nerve branches to the 3 canals are at least partially intact, prosthetic electrical stimulation encoding head motion should provide an effective means of partially restoring vestibular sensation and alleviating BVL symptoms.…”

“…Species-specific differences in sensitivity to aminoglycoside antibiotics could play a role, as could differences in gentamicin dose, route of delivery to the labyrinth, subject age, and duration since the onset of ototoxic injury. However, adult nonhuman primates treated with gentamicin at doses sufficient to permanently wipe out natural VOR responses can still have robust electrically evoked 3D VOR responses years later, despite postmortem histologic exam revealing absence of type I hair cells and absence of stereocilia on type II hair cells (12). Human subjects in this study may have had even more severe hair cell lesions, but the presence of some natural VOR responses to whole-body rotation preoperatively suggests that they had at least some hair cell and afferent neuron survival.…”

Characterization of pulse amplitude and pulse rate modulation for a human vestibular implant during acute electrical stimulation

“…In animal models, vestibular deficit is typically induced either by gentamicin treatment or canal plugging. Both render the semicircular canals insensitive to rotation, but leave the afferent fibers intact and excitable by electrical stimulation (Lewis et al 2010, Sun et al 2015. In addition, canal plugging is unlikely to alter the spontaneous firing rate, while gentamicin treatment can reduce it by 40% in chinchillas (Hirvonen et al 2005).…”

Analysis of Vestibular Labyrinthine Geometry and Variation in the Human Temporal Bone

“…Electrically evoked VOR (eVOR) induced by vestibular implants have also been realized to match the same frequency dependency of a normal human vestibular system (van de Berg et al, 2014 ). Histopathological examination has shown that multichannel vestibular prosthesis can target vestibular afferent fibers without damaging them (Sun et al, 2015 ).…”