Pre-habilitation Before Vestibular Schwannoma Surgery-Impact of Intratympanal Gentamicin Application on the Vestibulo-Ocular Reflex

Abstract

Background: Patients with vestibular schwannoma that show residual peripheral-vestibular function before surgery may experience sudden and substantial vestibular loss of function after surgical resection. To alleviate the sudden loss of peripheral-vestibular function after vestibular-schwannoma (VS) resection, pre-surgical intratympanic gentamicin application was proposed. Objective: We hypothesized that this approach allows for a controlled reduction of peripheral-vestibular function before surgery but that resulting peripheral-vestibular deficits may be canal-specific with anterior-canal sparing as observed previously in systemic gentamicin application. Methods: Thirty-four patients (age-range = 27-70 y) with unilateral VS (size = 2-50 mm) were included in this retrospective single-center trial. The angular vestibulo-ocular reflex (aVOR) was quantified before and after (29.7 ± 18.7 d, mean ± 1SD) a single or two sequential intratympanic gentamicin applications by use of video-head-impulse testing. Both aVOR gains, cumulative saccadic amplitudes, and overall aVOR function were retrieved. Statistical analysis was done using a generalized linear model. Results: At baseline, loss of function of the horizontal (20/34) and posterior (21/34) canal was significantly (p < 0.001) more frequent than that of the anterior canal (5/34). After gentamicin application, loss of function of the horizontal (32/34) or posterior (31/34) canal remained significantly (p ≤ 0.003) more frequent than that of the anterior canal (18/34). For all ipsilesional canals, significant aVOR-gain reductions and cumulative-saccadic-amplitude increases were noted after gentamicin. For the horizontal canal, loss of function was significantly larger (increase in cumulative-saccadic-amplitude: 1.6 ± 2.0 vs. 0.8 ± 1.2, p = 0.007) or showed a trend to larger changes (decrease in aVOR-gain: 0.24 ± 0.22 vs. 0.13 ± 0.29, p = 0.069) than for the anterior canal. Conclusions: Intratympanic gentamicin application resulted in a substantial reduction in peripheral-vestibular function in all three ipsilesional canals. Relative sparing of anterior-canal function noted at baseline was preserved after gentamicin treatment. Thus, pre-surgical intratympanic gentamicin is a suitable preparatory procedure for reducing the drop in peripheral-vestibular function after VS-resection. The reasons for relative sparing of the anterior canal remain unclear.

Keywords: aminoglycosides; anterior-canal sparing; tumor size; vestibulotoxicity; video-head-impulse testing.

Figure 1

Video-head-impulse testing before and after intratympanic gentamicin application is shown for two representative patients with unilateral VS. In (A) [patient #14, left-sided VS, max. diameter 20 mm as shown on axial T1-weighted contrast-enhanced MRI in (B)], baseline testing showed an overall normal aVOR response for all six SCCs with only very few saccades for the ipsilesional horizontal and posterior canal (only ipsilesional traces shown). One month after intratympanic gentamicin application (0.3 ml), vHIT demonstrates a significantly reduced aVOR gain for the left horizontal and left posterior SCC with accompanying overt catch-up saccades, whereas the left anterior canal remained functionally intact. In addition, low-amplitude, compensatory saccades are observed in the right horizontal and posterior SCC. In (C) [patient #32, left-sided VS, max. diameter 19 mm as shown on axial T1-weighted contrast-enhanced MRI in (D)], baseline testing indicated partial loss of function of the ipsilesional horizontal (with mild reduction in gain and overt catch-up saccades) and posterior (with normal gain but significant overt catch-up saccades) SCC, whereas anterior-canal function remained intact. Sixteen days after left-sided intratympanic gentamicin application (0.7 ml), gains of the ipsilesional horizontal and posterior canal had dropped sharply with covert and overt catch-up saccades having grown in amplitude as shown on vHIT. In addition, the ipsilesional (left) anterior SCC now demonstrated a partial loss of function with a mild decrease in gain and significant covert and overt catch-up saccades. However, in comparison to the left horizontal and posterior canal, the impairment in aVOR was clearly smaller for the left anterior canal, suggesting gentamicin-related anterior-canal sparing.

Figure 2

(A) Distribution of ipsilesional impairment in semicircular canal (SCC) function based on the two reviewers' ratings both at baseline (in blue) and after intratympanic gentamicin treatment (one or two treatments, individually different) (in red). In (B), the percentage of patients with normal function before and after gentamicin instillation (green areas) and with hypofunction based on the reviewers' overall ratings for the different SCCs [horizontal (H), anterior (A) and posterior (P)] are illustrated in a hexplot, differentiating between the ipsilesional (I) and the contralesional (C) side in the plot. Loss of function at baseline (indicated by the blue bars) is distinguished from new SCC hypofunction after intratympanic gentamicin application (indicated by the red bars); thus, the overall fraction of SCC impairment after gentamicin treatment is reflected by the red plus the blue fraction. In (C,D), the mean (±1 SD) changes (Δ) in aVOR gain (C) and CSA (D) after intratympanic gentamicin application compared to baseline measurements (i.e., by subtracting the aVOR gain/the CSA at baseline from the aVOR gain/CSA after gentamicin instillation) are illustrated for all six SCCs. Note that aVOR-gain reductions after gentamicin instillation will result in a negative Δ gain [as indicated along the y-axis in (C)]. Results of the statistical analysis (GLM) are shown for the ipsilesional (I) side only as there were no significant changes (p > 0.05) on the contralesional (C) side. Differences with a trend to significance were indicated by “*,” whereas significant (i.e., p < 0.05) differences were marked with a “**.”

Figure 3

Mean (±1SD) gains (A,C) and CSA (B,D) of all patients (n = 34) are shown separately for baseline (left column) and after gentamicin treatment (right column), with values from the affected [ipsilesional (I)] side and the unaffected [contralesional (C)] side indicated by gray and dark bars, respectively. Gain values (from 0 to 1) and CSA (°/trial, from 0 to 3) are provided along the different hexagons. Cutoff values for reduced gains (<0.8 for the horizontal canals, <0.7 for the vertical canals) and for abnormally increased cumulative saccade amplitudes (>0.73°/trial) are indicated by dashed lines. In (E–G), correlation analyses using principal component analysis (PCA) are shown both for the size of the VS and for the aVOR gain of the individual SSCs on the affected side at baseline (E), the difference (Δ) in aVOR gain (gain after 1st dose of gentamicin subtracted from gain at baseline) vs. baseline gain (F) and for the difference (Δ) in CSA (CSA at baseline subtracted from CSA after 1st dose of gentamicin) vs. baseline cumulative saccade amplitude (G). The diamonds (horizontal canals), squares (anterior canals), and inverted triangles (posterior canals) refer to single-subject and single SCC measurements; the solid black line represents the fit of the PCA, with details shown in the inlets [including the 95% confidence interval (CI) of the slope]. Note that individual results from the three ipsilesional SCCs are combined for the PCS.