Skull-vibration-induced nystagmus test in patients who are candidates for intratympanic gentamicin injection| ACTA Otorhinolaryngologica Italica

Abstract

Objective. This study aims to evaluate the utility of the skull-vibration-induced nystagmus test (SVINT) in the selection of patients with Ménière’s disease (MD) for intratympanic injection of gentamicin. To date the indications for this treatment have been based only on subjective elements.
Methods. A retrospective study was performed in 20 patients diagnosed with unilateral MD. SVINT were performed monthly and the evoked responses were evaluated. After 6 months, the results from patients who were candidates for gentamicin treatment (G group) were compared with those who did not need it (nG group). Correlation with Dizziness Handicap Inventory (DHI) score was evaluated.
Results. 120 tests were performed. Positive SVINTs were identified in 52 cases (43.3%) and included excitatory nystagmus in 18 (34.7%), inhibitory nystagmus in 28 (53.8%), and atypical pattern in 6 cases (11.5%). A significant increase excitatory nystagmus was recorded in group G (p = 0.00001). Moreover, there was a significant increase in the DHI score in group G compared with the nG group (p < 0.0001) and in patients with evoked excitatory nystagmus.
Conclusions. The finding of excitatory nystagmus during SVINTs performed on several occasions in the follow-up prior to intratympanic injection of gentamicin strengthens this therapeutic choice.

Introduction

Ménière’s disease (MD) is an inner ear disorder characterised by episodes of spontaneous vertigo usually associated with unilateral fluctuating sensorineural hearing loss, tinnitus and aural fullness.

Cochlear symptoms can also occur between vertigo episodes. The prevalence of MD is approximately 34-190 per 100,000 ^1-3. The onset of symptoms ranges from the third to the seventh decade of life with a slight female predominance. The aetiology of the disorder is not fully understood, but increased endolymphatic volume (hydrops) is the commonly accepted pathophysiological mechanism. This finding is also supported by recently developed imaging techniques ^4,5. MD is associated with various comorbidities such as autoimmune disorders ⁶ and migraine ⁷. In 2015, the Barany Society proposed the following diagnostic criteria for definite MD ⁸:

1. two or more spontaneous episodes of vertigo each lasting 20 minutes to 12 hours;
2. audiometrically documented low to medium frequency sensorineural hearing loss in one ear, defining the affected ear, on at least one occasion before, during, or after one of the episodes of vertigo;
3. fluctuating aural symptoms (hearing, tinnitus or fullness) in the affected ear;
4. not better accounted for by another vestibular diagnosis.

Vestibular evaluation does not offer any contribution to the diagnosis of the disease. Indeed, in the period between episodes, there are often no changes in the results of conventional tests. In the more advanced stages of the disease, it is more likely to find hypofunctional aspects as an expression of a progressive sensorineural deterioration on the vestibular side, similar to what occurs for cochlear function. Spontaneous nystagmus can be observed during episodes and the related vestibular tests give rise to responses that express a paretic (deficit) or irritative functional state. However, it is often possible to record opposing responses that express a functional dissociation in both the frequency (caloric vs video Head Impulse Test) and topographical domain (macular vs canal clinical signs) ^9,10.

The skull-vibration-induced nystagmus test (SVINT) is one of the methods recently introduced in clinical practice for the study of vestibular function ¹¹. In a recent analysis, it was the most sensitive vestibular test, provoking a consistent nystagmus beating on the healthy side in 58.7% of a large population of MD patients ¹². Intratympanic injection of gentamicin is widely used in the treatment of disabling unilateral MD. In this case, a profound vestibular deafferentation is required to obtain subjective improvement during treatment. A multifrequency vestibular study for this evaluation includes SVINT, head shaking test (HST) and caloric test ¹³. SVINT, in particular, is easy to apply and requires a short time for execution. For this reason, it can be used in the follow-up of patients undergoing intratympanic gentamicin treatment where it is desirable to evaluate the extent of vestibular deafferentation. Conversely, the indication for treatment with gentamicin in cases with poor therapeutic control of the disease is based exclusively on the symptoms reported by the patient. In fact, vestibular tests predicting the candidates for this treatment have not been described in the literature. From the previously mentioned features, SVINT could, in theory, demonstrate its utility.

The aim of this study was to establish a possible correlation between the oculomotor patterns evoked during SVINT, performed on several occasions during follow-up, and the degree of disability reported by patients. Consequently, we wished to verify the usefulness of the test in selecting patients for treatment with intratympanic injection of gentamicin. In this case, the hypothesis of an excitatory response as an expression of a recurrent or persistent functional condition, as opposed to deafferentation, could represent a condition resulting in vertigo episodes and the patient’s disability.

Materials and methods

A retrospective study was conducted on a population of 20 consecutive patients experiencing unilateral MD diagnosed in the period from January 30, 2016 to March 6, 2021. All patients met diagnostic criteria for definite MD according to the Barany Society ⁸. Patients who followed a personal protocol for monitoring the disease and accepting the therapeutic option were included in the study. This protocol included monthly clinical tests for 6 months after diagnosis of the disease. All patients underwent the same therapy during the entire period and were invited to write a diary detailing the vertigo episodes that occurred. On the occasion of each monthly control, in addition to a global audiological and vestibular evaluation, including caloric and video-Head Impulse test (vHIT), SVINTs were performed. At the end of the follow-up, the Dizziness Handicap Inventory (DHI) was administered to each patient for subjective assessment of the degree of disability ¹⁴. Finally, patients were asked whether the therapeutic measures adopted were considered to be satisfactory. In those dissatisfied with clinical control, treatment with intratympanic gentamicin was considered as an alternative treatment. In these patients, the treatment was reserved for those with sensorineural hearing loss with pure-tone audiometry > 50 dB and serviceable hearing in the contralateral ear. Vestibular impairment on the unaffected side was excluded by a complete vestibular evaluation. The results that emerged from each test, at the planned control visits, were entered into a database from which the data were extracted for statistical evaluation.

Patients with clear migraine comorbidity were excluded from the study, and received a different medical therapy. A brain imaging study (MRI with or without gadolinium, angio MRI) was performed in all patients to exclude acoustic schwannoma or neurovascular conflicts and a high-resolution CT of the petrous bone for interruptions of the otic capsule. SVINT was performed at a frequency of 100 Hz with an oscillation amplitude of 0.8 mm for each cycle. The vibrator was applied and held firmly perpendicular to the skin above the mastoid process, posterior to the auricle, at the level of the external acoustic meatus. Three stimulations were performed on each mastoid lasting 5-10 seconds each ¹⁵. Eye movements were studied with Frenzel video glasses and visual fixation of both eyes was denied. The test was considered positive when the same type of nystagmus was evoked in all six tests. According to the evoked oculomotor response, the following patterns were considered:

1. normal pattern: no nystagmus evoked during SVINT;
2. pathological pattern: nystagmus evoked during SVINT.

As part of the pathological pattern, the following have been identified:

1. inhibitory type: evoked nystagmus (purely or mainly horizontal) beating towards the unaffected (healthy) side;
2. excitatory type: evoked nystagmus (purely or mainly horizontal) beating towards the affected side;
3. atypical type: evoked nystagmus (not purely or mainly horizontal) with clear vertical and/or torsional components.

The global incidence of normal and pathological patterns (Inhibitory, Excitatory and Atypical) was calculated in all patients who completed the protocol. A comparative assessment was made between the group of patients who were candidates for treatment with intratympanic injection of gentamicin (group G) and the group of patients not candidates for this treatment (group nG). At the same time, the DHI scores that emerged in the two groups (G vs nG) were compared. Furthermore, the DHI scores and the number of vertigo episodes were compared between the group of patients with at least one pathological pattern of excitatory type (Exc group), which emerged in at least one of the tests performed, and those who never presented this type during the protocol (nExc group). At each control, cases were considered in whom at least one vertigo episode was reported within the previous 3 days, or within the following 3 days, or within the previous and the following 3 days. In this way, the correlation of these cases with the oculomotor pattern evoked at SVINT was assessed. The statistical evaluation compared the percentages of the parameter under examination between groups using the chi-squared test. Comparison of means (M) and standard deviations (SD) of the DHI and the vertigo episodes were made using a t-test. The level for a statistically significant difference between groups was taken as p < 0.05.

Results

Of the 23 patients initially enrolled after diagnosis of MD, three dropped out of follow-up. Of these, two presented with recurrent paroxysmal positional vertigo which required a different treatment and one patient was affected by COVID-19. The remaining 20 patients were considered eligible for the study as they completed the series of tests provided and followed the proposed therapeutic indications. In 8 patients (group G), the results after intratympanic injection of gentamicin were taken into consideration as the results obtained from therapy were inconsistent. Treatment with gentamicin was proposed in six of these patients as they had unilateral hearing loss and a normal contralateral vestibular function. All accepted the therapeutic measure. On the other hand, the results from 12 patients were satisfactory and they did not require treatment with gentamicin (group nG).

A total of 120 SVINTs were performed monthly for 6 months in the 20 patients recruited for this study (20 patients undergoing 6 monthly tests). A normal pattern emerged in 68 (56.7%) cases and a pathological response in 52 (43.3%), including 28 Inhibitory type, 18 Excitatory type and 6 Atypical type (Tab. I). The correlation between SVINT and the results of caloric and vHIT are shown in Figures 1 and 2. The incidences of subtypes within the pathological oculomotor response were 53.8, 34.7 and 11.5%, respectively, for the Inhibitory, Excitatory and Atypical types. Among the 48 SVINTs performed in the 8 patients in group G, a normal pattern was recorded in 20 cases (41.7%) and a pathological pattern in 28 (58.3%), of which there were 6 of the Inhibitory type (6/48:12.5%), 16 Excitatory type (16/48: 33.3%) and 6 Atypical (6/48: 12.5%). In the 72 SVINTs performed in the 12 patients in the nG group, a normal pattern was identified in 48 (66.7%) controls and a pathological pattern in 24 (33.3%), of which 22 were of the Inhibitory type (22/72: 30.5%), 2 Excitatory type (2/72: 2.8%) and none of the Atypical type. A significant increase (p = 0.00678) in the pathological oculomotor pattern (chi-squared test) was therefore observed in the G group. Comparison between oculomotor patterns in group G showed a significant increase in the Excitatory type compared to that of the Inhibitory type (p = 0.00001). On the other hand, in patients belonging to the nG group, the oculomotor pattern of Inhibitory type appeared to be significantly increased compared to that of Excitatory type (p = 0.0001). Over the follow-up period, the mean number of vertigo attacks in the Exc group was 15.6 ± 9.90, which was significantly higher (p = 0.0019) than in the nExc group (4.17 ± 2.69) (Tab. II). At 39 controls (32.5%), patients reported at least one vertigo episode within 3 days, before and/or after the control itself. In particular, vertigo occurred in the 3 previous days in 20 cases and in the 3 following days in 10 cases. In the remaining 9 cases, at least one vertigo episode was recorded in both the previous and the following 3 days at the control. A positive SVINT emerged in 29 (74.3%) of these 39 controls, of Inhibitory, Excitatory and Atypical type in 11, 12 and 6 cases, respectively. In the 11 cases of Inhibitory type, vertigo episodes always occurred in the 3 days preceding the control and never in the following 3 days (Tab. III). Statistical evaluation showed a significant increase in the incidence of positive SVINTs in the series of 39 controls performed closer to the vertigo episode compared to those in which vertigo occurred outside the time range considered (p < 0.00001). In particular, in the series of controls closer to the vertigo episode, there was a significant increase in the incidence of Excitatory (p = 0.00078) and Atypical (p = 0.00195) types compared to the series of controls in which vertigo occurred outside the considered time range. On the other hand, no significant difference emerged between the incidence values of the Inhibitory type between the series of controls performed closer to the vertigo episode compared to the series in which vertigo occurred outside the considered time range (p = 0.7666). The overall mean DHI score in the patients enrolled in the study was 41.8 ± 9.2 (55.5 ± 7.66 in the G group and 32.66 ± 7.58 in the nG group). A mean DHI score of 51.8 ± 8.7 was recorded in patients who presented at least one Excitatory type response on one or more of the SVINTs performed. The score was 29.2 ± 9.3 in the group of patients who never presented Excitatory type responses on SVINT. Therefore, there was a significant increase (p < 0.0001) in the DHI score in group G (group G vs group nG) and in the Exc group (Exc group vs nExc group).

Discussion

Intratympanic injection of gentamicin is one of the treatments commonly used in unilateral disabling MD. Intractable MD is defined when patients have more than one severe vertiginous episode per month with repetitive episodes for more than 6 months, despite conservative medical management ¹⁶. On this basis, the temporal criterion adopted by us in the follow-up of MD patients appears to be justified. Several studies highlight the favourable results obtained following treatment with different types of local application, related to therapeutic control of the disease and preservation of hearing threshold ^13,17-19. To date, the indication for this treatment is based on subjective elements, in the absence of clinical markers resulting from conventional vestibular tests applied in clinical practice. However, complete bilateral objective evaluation of vestibular function is always required, especially in the elderly, prior to administering intratympanic gentamicin. This in order to avoid the possible outcome in bilateral vestibulopathy when the opposite side is hypo-reflective.

On the other hand, SVINT is a useful tool to evaluate the severity of the deafferentation after intratympanic gentamicin application. A preferential action, with a relative vestibulotoxic effect, has been demonstrated for gentamicin on irregular sensory cells of type I, which are more sensitive to high frequency vibratory stimuli ²⁰. After one injection, Junet et al. observed a positive SVINT beating toward the unaffected side in 75% of patients treated for disabling MD. After 7 injections, the same authors reported the same results in all of the patients examined ¹³. SVINT represents a method that is easy to perform, rapid, inexpensive, of unequivocal interpretation and above all, unlike the caloric test, well tolerated. As reported in the literature, SVINT is the most sensitive test to detect an imbalance in the vestibular system during the intercritical period outside vertigo episodes ¹². Our data are consistent with those reported in the literature.

In a recent paper, SVINT was seen to be more sensitive compared to vHIT, provoking a consistent nystagmus beating toward the unaffected side in 301 of 511 patients recruited (58.7%), apart from two cases in whom the nystagmus direction was toward the hydropic side ¹². Hong et al. analysed 52 MD and observed a positive SVINT in 71% of patients; in many cases (27%), the evoked nystagmus was beating toward the lesion side ²¹. Dumas et al. described a positive SVINT in 71% of patients with MD, mostly observed in a period closer to the vertigo episode ²². Those authors also reported an excitatory nystagmus in 15.8% and a frequent discordance with caloric and head shaking test ²³. Caloric tests in patients suffering from MD generally shows impairment of the affected side in presence of a normal or slightly increased VOR. A recent paper attributed this to the hydropic enlargement of the membranous labyrinth ²⁴. It is possible that the physical modification induced by hydrops could make the vestibule more sensitive to vibratory stimulus and less responsive to caloric ones. This may explain the dissociation between calorics and SVINT and the presence of the excitatory pattern. However, as SVINT is the only test that evaluates the higher frequencies, it cannot be excluded that excitatory pattern is the sign of a selective suffering of vestibular receptors. In the present work, the presence of this pattern seems to be associated with the crisis as sign of an altered state of the labyrinth. This is consistent with the studies of Lee et al. that reported a higher percentage of excitatory pattern when the tests were performed close to a crisis ²⁵, while Teggi et al., who evaluated patients only during a vertigo free period, described nystagmus beating towards the affected side only in 1% of cases. For these reasons, SVINT can be considered a simple aid to monitor vestibular function in patients suffering from MD and provide valid feedback on the response to therapy, even if it must always be integrated with a complete bilateral vestibular evaluation.

The aim of this study was to examine the usefulness of the SVINT in providing objective data that can support the decision to administer intratympanic gentamicin based on anamnestic elements in those cases not responsive to medical therapy. The main finding of our study is represented by the higher incidence of vestibular alterations, identified by the SVINT during controls, in patients with MD who, at the end of the follow-up, needed intratympanic gentamicin injection. In particular, excitatory-type responses are more frequently expressed in these patients. In the irritative phase, the disease may enhance the response of afferent neurons ²⁶ which causes an imbalance in neural activity between the two vestibular nuclei and thus results in nystagmus beating toward the affected side ²⁷. The finding of a hyperfunctional state that persists even outside the episode could represent a trigger for new episodes and, at the same time, favour a condition of chronic dizziness. In fact, this study shows that the finding of an excitatory pattern, during the pre-established controls, significantly increases the possibility of an imminent crisis in subsequent days. On the other hand, the finding of a higher incidence of deficient oculomotor patterns in which treatment with intratympanic gentamicin was not considered necessary would seem to indicate a quiescent functional state favourable to the clinical course and, in general, there is a good response to the therapeutic measures adopted. The hypothesis of a hyperfunctional state responsible for the symptoms of MD is also confirmed by DHI, which reveals a greater degree of subjective disability in these patients. The final dataset considered in this study is related to the occurrence of atypical patterns induced by the SVINT and which, although not frequent, require some speculative interpretation. The presence of torsional and/or vertical components that replace or increase the horizontal component of the nystagmus, and which are more frequently identifiable, could be explained by a greater involvement of the endolymphatic hydrops in the posterior labyrinth with involvement of more ampullary and/or macular receptors. In all six cases recorded in our study, occurrence of this pattern during SVINTs carried out in close temporal relationship with vertigo episodes makes this hypothesis more credible. The constant association with excitatory-type responses in the same patient, evoked during SVINTs performed at different times, seems to impart an unfavourable prognostic significance for the Atypical pattern. Execution of the SVINT during vertigo crises, although difficult to achieve, is necessary to confirm the hypothesis that the Atypical pattern may represent a semiological marker of symptomatic endolymphatic hydrops. At the same time, a greater number of cases is required to confirm the association of the above-mentioned patterns in the same patient and to hypothesise different occurrences of the same functional condition which inevitably leads to the implementation of alternative therapeutic measures, such as intrantympanic injection of gentamicin.

Conclusions

Treatment with intratympanic injection of gentamicin represents a useful measure in cases of unilateral defined MD that do not respond to medical therapy and to the adoption of behavioural and dietary remediation. The indication for this treatment is based exclusively on subjective elements. SVINT represents a useful method to consolidate the therapeutic choice as a sensitive test. The finding of an excitatory-type oculomotor response pattern during SVINTs performed on several occasions in the follow-up period before the administration of gentamicin provides useful information in defining patients who are candidates for this treatment.

Conflicts of interest statement

The authors declare no conflict of interest

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author contributions

GC, ADG, MF: work conception, research, design of the study, data collection, writing of the main body of the manuscript; GC, ADG, MF, VEP, GR: data analysis and interpretation, critical revise for important intellectual content, final approveal of the version to be published; LC, CP: data collection, critical revise for important intellectual content, final approveal of the version to be published.

Ethical consideration

Ethical approval was waived by the local Ethics Committee of the University of Perugia in view of the retrospective nature of the study, and all the procedures performed were part of routine care. The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s Declaration of Helsinki. Written informed consent was obtained from each patient for study participation and data publication.

Figures and tables

Figure 1.Pathological response to SVINT, caloric and vHIT. The distribution of the pathological responses among the 20 recruited patients is illustrated on the abscissa. The ordinate illustrates the number of pathological responses to vestibular tests at the six controls performed by each patient.

Figure 2.Distribution of the oculomotor patterns within patients with pathological responses to SVINT (52), caloric (22) and vHIT (14) during the six controls performed by each patient. As part of the pathological responses that emerged from the caloric test, only an Inhibitory type pattern was recorded (hypo-reflective affected side). Conversely, an Excitatory pattern (VOR gain > 1) also emerges in the pathological responses to vHIT (hyperreflective affected side). Atypical nystagmus evoked is an exclusive SVINT response.

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