Direct entry of gadolinium into the vestibule following intratympanic applications in Guinea pigs and the influence of cochlear implantation

Abstract

Although intratympanic (IT) administration of drugs has gained wide clinical acceptance, the distribution of drugs in the inner ear following IT administration is not well established. Gadolinium (Gd) has been previously used as a marker in conjunction with magnetic resonance imaging (MRI) to visualize distribution in inner ear fluids in a qualitative manner. In the present study, we applied gadolinium chelated with diethylenetriamine penta-acetic acid (Gd-DTPA) to the round window niche of 12 guinea pigs using Seprapack(TM) (carboxlmethylcellulose-hyaluronic acid) pledgets which stabilized the fluid volume in the round window niche. Gd-DTPA distribution was monitored sequentially with time following application. Distribution in normal, unperforated ears was compared with ears that had undergone a cochleostomy in the basal turn of scala tympani and implantation with a silastic electrode. Results were quantified using image analysis software. In all animals, Gd-DTPA was seen in the lower basal scala tympani (ST), scala vestibuli (SV), and throughout the vestibule and semi-circular canals by 1 h after application. Although Gd-DTPA levels in ST were higher than those in the vestibule in a few ears, the majority showed higher Gd-DTPA levels in the vestibule than ST at both early and later time points. Quantitative computer simulations of the experiment, taking into account the larger volume of the vestibule compared to scala tympani, suggest most Gd-DTPA (up to 90%) entered the vestibule directly in the vicinity of the stapes rather than indirectly through the round window membrane and ST. Gd-DTPA levels were minimally affected by the implantation procedure after 1 h. Gd-DTPA levels in the basal turn of scala tympani were lower in implanted animals, but the difference compared to non-implanted ears did not reach statistical significance.

FIG. 1

A Gd-DTPA uptake into the inner ear of the guinea pig. Scan time 32 min; Gd-DTPA application time 3 h and 7 min; both ears intact, no implantation. B–E The right inner ear with regions of interest (ROI) marked by magenta outlines; OW oval window, Post V posterior vestibule, Ant Vest anterior vestibule, SV-LB scala vestibuli lower basal turn, ST-LB scala tympani lower basal turn, SV-UB scala vestibuli upper basal turn, ST-UB scala tympani upper basal turn, SV-L2 scala vestibuli lower second turn, ST-L2 scala tympani lower second turn, SV-U2 scala vestibuli upper second turn, ST-U2 scala tympani upper second turn, SV-L3 scala vestibuli lower third turn, STL3 scala tympani lower third turn, SV-U3 scala vestibuli upper third turn, ST-U3 scala tympani upper third turn, Apex apical turn.

FIG. 2

Measurement and quantification of Gd-DTPA distribution patterns at 60 min after application to the RW niche. A Serial MR sections of a non-implanted ear in which the brightest region occurs at the basal part of ST. b Quantified brightness levels in ST and SV for the specimen shown in (a). Abscissa represents inner ear location, ordinate represents brightness (see “Materials and methods”). LB lower basal turn; UB upper basal turn; L2 lower second turn; U2 upper second turn; L3 lower third turn; U3 upper third turn; Apex apical turn. C A left, non-implanted ear showing brightest region in SV. D Brightness levels in ST and SV quantified for specimen shown in (C). E A right, non-implanted ear showing brightest regions in the vestibule and SV. F Brightness levels in ST and SV quantified for specimen shown in (E). G Anatomic representation of compartments for comparable sections derived from a 3D reconstruction of the inner ear. Light orange ST; Dark orange SV; blue endolymphatic space; brown stapes footplate; light green spiral ligament; medium green modiolos; dark green facial nerve; red cochlear aqueduct. H Illustration of the entire 3D rendered model from which the slices shown in (G) are taken

FIG. 3

Average brightness distribution at 10 defined locations in control ears. A 1 h after Gd-DTPA application to RW niche. Closed dots represent SV, and open squares represent ST. N = 15. B Brightness differences between SV and ST after 1 h. In the basal turn, SV is typically brighter than ST, suggesting higher Gd-DTPA levels there. C 2.5 h after Gd-DTPA application to RW niche. N = 15. D Brightness differences between SV and ST after 2.5 h. At this time, SV is significantly brighter than ST in the lower basal turn.

FIG. 4

Average brightness distribution at 10 defined locations in implanted ears. A 1 h after Gd-DTPA application to RW niche. Closed dots represent SV, and open squares represent ST, N = 9. B Brightness differences between SV and ST after 1 h. C 2.5 h after Gd-DTPA application to RW niche. Closed dots represent SV, and open squares represent ST. N = 9.B Brightness differences between SV and ST after 2.5 h. At this time, both the lower and upper basal turns of SV are significantly brighter than the adjacent regions of ST.

FIG. 5

Calculated Gd concentration profiles as a function of inner ear location and time. Each row (ST and SV, which includes the vestibule) represents a specific condition. A Calculated Gd levels in ST and SV, respectively, when all drug enters through the RW membrane. B Calculated Gd levels in ST and SV, respectively, when 50% of the drug enters through the RW membrane and 50% enters the vestibule in the area of the stapes. SV concentrations remain lower than those in ST because of the larger perilymph volume in the SV compartment relative to ST. C Calculated Gd levels in ST and SV, respectively, when just 10% of the drug enters through the RWM, and 90% enters via the stapes. The higher level seen in SV relative to ST is comparable to that found experimentally.