Intratympanic Gentamicin Application Research Articles

Vestibular and audiometric results after endolymphatic mastoid shunt surgery in patients with Menière’s disease

PurposeTreatment of Menière’s Disease (MD) comprises an array of both non-destructive and destructive treatment options. In patients who are therapy–refractory to non-destructive medical treatment, endolymphatic mastoid shunt surgery (EMSS) is both recommended and debated controversially. The aim of this study was to investigate safety in terms of hearing, vestibular function, complication rate, and efficacy with regards to vertigo control of EMSS in patients with MD according to the current diagnostic criteria of 2015.MethodsRetrospective analysis of 47 consecutive patients with definite or probable MD with description of demographic parameters, pre- and postoperative MD treatment, pre- and postoperative audiometric (pure tone audiometry) and vestibular (caloric testing) results. The parameters were compared between patients with and without postoperative vertigo control.Results31/47 patients (66.0%) had improved vertigo control postoperatively. Postoperative hearing and vestibular preservation were predominantly stable. No significant differences between patients with improved vertigo control and patients with no change or worse vertigo episodes were found. In the treatment refractory group, 4 patients required a revision EMSS and 6 a destructive MD treatment (5 gentamicin intratympanically, 1 labyrinthectomy). No peri- or postsurgical complications were reported.ConclusionsEMSS was found to be beneficial in two thirds of the patients with definite or probable Morbus Menière and a safe procedure regarding hearing and vestibular preservation with no postoperative complications. Therefore, EMSS should be considered before inducing destructive treatment options, such as intratympanic gentamicin application or labyrinthectomy.

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

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.

The evaluation of vestibular compensation by vestibular rehabilitation and prehabilitation in short-term postsurgical period in patients following surgical treatment of vestibular schwannoma.

Vestibular schwannoma removal causes unilateral vestibular deafferentation, which results in dizziness and postural unsteadiness. Vertigo and balance problems together are among the most important aspects affecting quality of life. Intensive vestibular rehabilitation, which starts before surgery, with following postsurgical supervised rehabilitation, using visual biofeedback propose an instrument to accelerate a recovery process. Another option how to accelerate the vestibular compensation, is employment of presurgical gentamicin ablation together with vestibular rehabilitation (prehabilitation) of vestibular function. Purpose of present study was to examine the dynamics of vestibular compensation process using supervised intensive vestibular rehabilitation with visual biofeedback in the short-term postsurgical period. The second aim was to compare both studied groups mainly to evaluate if prehabilitation has potential to accelerate the compensation process in the early postoperative course. The study included 52 patients who underwent the retrosigmoid vestibular schwannoma removal. They were divided into two groups. The first group was prehabilitated with intratympanic application of gentamicin before surgery to cause unilateral vestibular loss (14 patients), the second group (38 patients) was treated in standard protocol without prehabilitation. All patients underwent at home vestibular training before surgery to learn new movement patterns. Following the surgery supervised intensive vestibular rehabilitation including visual biofeedback was employed daily in both groups between the 5th and 14th postoperative day. Outcome measurements included an evaluation of subjective visual vertical (SVV), posturography and the Activities-Specific Balance Confidence Scale (ABC). ANOVA for repeated measurements was used for statistical analysis. We observed significant improvement in SVV (p < 0.05), posturography parameters (p < 0.05) and ABC scores (p < 0.05) with postoperative rehabilitation program following surgery in both groups. There was no statistically significant difference between group treated by prehabilitation and group without prehabilitation. Results of this study showed that intensive postsurgical rehabilitation represents key factor in compensation process following retrosigmoid vestibular schwannoma surgery. Prehabilitation did not speed up recovery process.

Intratympanic Gentamicin Versus Labyrinthectomy: Inner Ear Sensitivity to Gentamicin and Impact on the Contralateral Labyrinth.

Objectives.To investigate the impact of labyrinthectomy and intratympanic (IT) gentamicin injections on the contralateral labyrinth, we also assessed the response of each individual semicircular canal to each IT gentamicin application.Methods.We performed a pilot observational study on tertiary, referral, academic settings. Thirteen patients with unilateral vestibular pathology were organized into two groups, group I (seven patients) receiving IT gentamicin and group II undergoing labyrinthectomy (six patients). All patients underwent six-canal video-head-impulse test in predetermined time intervals. Patients receiving gentamicin were additionally tested 3 to 5 days after every sequential injection, until all ipsilateral canals were ablated, to determine the order of response to gentamicin. We recorded the vestibular-ocular reflex gains and the presence of covert/overt saccades for each canal.Results.The posttreatment ipsilateral gains were abnormal. No patient from the gentamicin group developed abnormal contralateral responses, while patients undergoing labyrinthectomy had abnormal contralateral responses from at least one canal, even several months posttreatment. Finally, the lateral semicircular canal was the first one to be affected by IT gentamicin followed by the posterior canal: the superior canal was ablated last.Conclusion.In our study, labyrinthectomy had an impact on the responses recorded from the contralateral ear, while IT gentamicin ablated the ipsilateral labyrinthine function without affecting the contralateral responses, possibly because of a milder, more gradual impact. We also show for the first time the order that IT gentamicin application affects the semicircular canals, with the lateral being the first to be affected.

Menière's Disease

Menière`s disease is one of the most common inner ear and vestibular disorders. It is defined as the idiopathic syndrome of endolymphatic hydrops (ELH). Despite the development of several different animal models of ELH, its etiology and pathogenesis is still unresolved. In humans, endolymphatic hydrops may occur spontaneously or as a consequence of specific disorders with distinct inner ear pathologies, e. g., infectious labyrinthitis, noise induced hearing loss or vestibular schwannoma. Recent imaging studies using MRI have shown that hydropic ear disease is associated not only with the full triad of vertigo, hearing, loss and tinnitus/aural pressure, but also with inner ear symptoms that do not fulfill the clinical criteria of definite Menière's disease as set forth by the AAO-HNS. Therefore, terms like "atypical" or "cochlear"/"vestibular" Menière's disease or "forme fruste" should be avoided and the term "Menière's disease" should universally be applied according only to these guidelines. Besides that, the recent possibility of visualizing endolymphatic hydrops on MRI and thereby ascertaining the diagnosis in difficult cases and new audiovestibular function tests for the indirect detection of endolymphatic hydrops show promising results. Evidenced based reviews of currently available therapeutic options still reveal many uncertainties with regard to efficacy, with the exception of the ablative therapies, e. g., intratympanic gentamicin application.

Does intratympanic gadolinium injection predict efficacy of gentamicin partial chemolabyrinthectomy in Menière’s disease patients?

Using actual diagnostic criteria, the diagnosis of certain Menière's disease remains impossible during life without histopathologic confirmation. Assessing the value of a diagnostic test is difficult due to the lack of a gold standard. Recent studies reported on the use of MRI after intratympanic gadolinium injection to demonstrate endolymphatic hydrops in vivo. We evaluate whether MRI after intratympanic gadolinium administration is useful for predicting the effect and outcome of intratympanic gentamicin therapy. The correlation between transtympanic electrocochleographic (TT-ECoG) results and hydrops grade on MRI images is also investigated. Twelve definite Menière's disease patients with incapacitating vertigo attacks, not responding to drug and behavioral treatment, were selected for partial chemolabyrinthectomy with intratympanic gentamicin. All patients underwent transtympanic electrocochleography followed by surgical middle ear inspection, partial chemolabyrinthectomy (gentamicin solution 40 mg/ml applied during 60 min) and intratympanic gadolinium injection with clear exposure of the round window membrane. The MR images were reviewed and a hydrops grade was assigned. Correlation between the hydrops grade and the electrocochleographic data was assessed. Only 5 of 12 patients showed gadolinium enhancement in the inner ear. However, 6 of the 7 patients that did not show postoperative intracochlear or intralabyrinthine gadolinium distribution did report the clinical improvement after intratympanic gentamicin therapy. Hydrops grade correlated with the result of transtympanic electrocochleography in four of five cases that showed gadolinium enhancement. We conclude that the use of intratympanic gadolinium has no added value in predicting the clinical outcome of intratympanic gentamicin application. However, based on these data, a correlation between the result of TT-ECoG and hydrops grading on MRI images can be suggested.

Intratympanic gentamicin for Ménière's disease or syndrome

Ménière's disease is characterised by three major symptoms: vertigo, deafness and tinnitus, which may be accompanied by aural fullness, all of which are discontinuous and variable in intensity. While discontinuous, these symptoms are synchronous. Intratympanic application of gentamicin, an ototoxic aminoglycoside, is a relatively new ablative treatment for vertigo in Ménière's disease with promising results. To assess the effectiveness of intratympanic gentamicin in the treatment of vertigo in Ménière's disease. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 30 June 2010. All randomised or quasi-randomised controlled trials of intratympanic gentamicin versus placebo, or versus another treatment for Ménière's disease. Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information. We identified two trials, involving 50 participants, which fulfilled the inclusion criteria. Both of these trials are prospective, double-blind, placebo-controlled randomised clinical trials on the effect of intratympanic gentamicin on vertigo complaints. Both of these trials found a significant reduction in vertigo complaints in the gentamicin group when compared to the placebo group. Due to clinical heterogeneity we could not perform a meta-analysis. Based on the results of the two included studies, intratympanic gentamicin seems to be an effective treatment for vertigo complaints in Ménière's disease, but carries a risk of hearing loss.

Gentamicin alters nitric oxide production in semicircular canals and otolith organs

Intratympanic application of gentamicin is an important therapeutic option to control vertigo spells in Ménière's disease. Low doses eliminate the function of semicircular canal ampullae (SCCA) and saccule in most patients, although utricular function is maintained in many cases. Local alteration in free radical production might be responsible for these differences. Therefore, the gentamicin-induced nitric oxide (NO) production was determined in an animal model using separate organ cultures of SCCA, saccule, and utricle. Prospective pilot study in male guinea pigs. SCCA, saccule, and utricle of 28 guinea pigs were isolated and incubated separately for 6 hours in cell culture medium. Gentamicin was administered in two different concentrations (0.4 mg/mL and 0.8 mg/mL) to organ cultures of 16 animals. Tissues from 12 animals were used as controls. Nitric oxide was quantified by chemiluminescence. Gentamicin led to an NO increase of about 70% in the saccule, an NO reduction of more than 70% in SCCA, and an NO reduction of 36% in the utricle. The selective effects of gentamicin on the NO production in the different sensory areas of the vestibular organ have to be taken into account in the therapy of Ménière's disease.

Effects of gentamicin on guinea pig vestibular ganglion function and on substance P and neuropeptide Y

Previous studies have demonstrated that following intratympanic gentamicin application in the guinea pigs, vestibular evoked myogenic potentials (VEMPs) were absent regardless of stimulation mode using either air-conducted sound (ACS) stimuli or galvanic vestibular stimulation (GVS). Ultrastructurally, both type I hair cells and their calyx terminals were distorted in the saccular macula. However, little is known about the toxic effects of gentamicin on the vestibular ganglion (VG). In this study, absent ACS- and GVS-VEMPs were noted in all the gentamicin-treated ears (100%), which were confirmed by the substantial loss of sensory hair cells in the saccular macula. Moreover, dramatic up-regulation of growth associated protein-43 (GAP-43) expression was detected in the ipsilateral VG neurons. The mean percentage of substance P-like immunoreactive (SP-LI) neurons in the treated VG (81.8 ± 1.9%) was significantly higher than that in the control VG (68.6 ± 3.3%). Conversely, the mean percentage of neuropeptide Y-like immunoreactive (NPY-LI) neurons in the treated VG (13.7 ± 3.8%) was dramatically lower than that in the control VG (49.0 ± 3.8%). Double labeling results shown 82% of SP-LI and 16% of NPY-LI neurons coexpressed with GAP-43, suggested that SP accumulating coincided with NPY decreasing in regenerating VG neurons after gentamicin treatment. Overall, the changes in SP and NPY expression in VG neurons after gentamicin treatment were like to those in the superior cervical ganglion following sympathectomy.

Surgical therapy in Menière’s disease

After P. Meniere's first description of the typical symptoms in 1861 it took more than 40 years before the first otosurgical procedures were performed to cure Meniere's disease. Various surgical methods were established during the twentieth century, which still are employed in the treatment of intractable Meniere's disease, especially saccotomy and vestibular neurectomy but also intoxication of the labyrinth by intratympanic application of gentamicin. Despite the good results of such therapeutic regimens the basic pathological mechanism is still not fully understood. Since the description of an endolymphatic hydrops by Hallpike und Cairns in 1938 as a typical feature, there have been some observations of a possible infectious, allergic and autoimmunological (co)pathogenesis without enough proof to explain the disease in every case. This article aims to present the current scientific data, diagnostics and therapy of Meniere's disease with special emphasis on surgical treatment options.

Time course of apoptotic cell death in guinea pig cochlea following intratympanic gentamicin application

Conclusions. The present study showed that the molecular signal that promotes the death of cochlear hair cells (HCs) induced by intratympanic gentamicin application is significant before the manifestation of morphological and functional changes. Objectives. The effect of agents that protect the HCs from aminoglycoside ototoxicity is influenced by the timing of their administration. However, morphological, functional and molecular changes in the cochlea in the early stage following aminoglycoside application have rarely been studied. Therefore, we examined the chronological changes in the cochlea following intratympanic gentamicin application. Materials and methods. Small pieces of gelatin sponge soaked with gentamicin (40 mg/ml) were placed on the round window membrane of mature guinea pigs, and the tympanic bulla was filled with gentamicin solution. They were euthanized at 6, 12, 18, 24, and 48 h following gentamicin application. Auditory brainstem responses (ABRs) were measured before gentamicin application and immediately before euthanasia, and the extent of missing and TUNEL-positive HCs was evaluated. Results. ABR thresholds significantly increased 18 h or later following gentamicin application, and the loss of HCs was seen at 24 and 48 h. While functional and morphological changes were not evident until 18 h after gentamicin application, substantial amounts of TUNEL-positive HCs appeared at 12 h.

Intratympanic gentamicin therapy for control of vertigo in unilateral Menière's disease: a prospective, double-blind, randomized, placebo-controlled trial

Conclusions. Intratympanic application of gentamicin is a relatively safe and efficient treatment for the reduction of complaints of vertigo attacks associated with Menière's disease. The treatment also reduces the severity of the perceived aural fullness. Objective. To investigate the effectiveness of intratympanic gentamicin treatment in patients with unilateral Menière's disease. Subjects and methods. In a prospective, double-blind, randomized, placebo-controlled clinical trial subjects scored vertigo complaints, aural fullness and tinnitus, before, during and up to 1 year after treatment. Hearing loss was monitored with pure tone audiometry. Results. Gentamicin treatment resulted in a significant reduction of the score for vertigo complaints and the score for perceived aural fullness. A small increase in hearing loss (average 8 dB) was measured in the gentamicin group.

Treatment of Ménière's Disease by Low‐Dosage Intratympanic Gentamicin Application: Effect on Otolith Function

The intratympanic application of a low dosage of gentamicin is increasingly favored as treatment for Ménière's disease. While posttreatment observations have confirmed a long-term success of the therapy of vertigo attacks, clear differences in the posttreatment recovery interval can be observed. In addition to differences in central-vestibular compensation, the degree of peripheral vestibular damage, i.e., to the saccule, utricle, and semicircular canal ampullae, varies among patients. This study provides comprehensive pre- and posttreatment results from unilateral functional tests of the individual vestibular receptors and of the cochlea in patients with Ménière's disease. Prospective clinical study. Nineteen patients with unilateral Ménière's disease were treated by intratympanic application of gentamicin by injection of 0.3 mL (12 mg) through the tympanic membrane under local anesthesia. Tests were performed immediately previous to treatment and subsequently in the periods 4 to 8 weeks and 12 to 16 weeks after treatment. Unilateral saccular function was tested by means of acoustic-click, vestibular-evoked myogenic potentials (VEMP), and unilateral utricular function by subjective visual vertical (SVV) during unilateral centrifugation. Bithermal caloric testing was performed to assess unilateral semicircular canal function. Prior to gentamicin treatment, the caloric response from the diseased ear was normal in 3 patients, below normal in 14 patients, and in 2 cases almost completely absent. VEMP responses could be recorded bilaterally in 13 patients; while in 6, no VEMPs could be measured from the diseased ear. Utricular function measured by SVV estimation was found to be normal in 11 patients and marginally abnormal in 2 patients. In six cases, the SVV was clearly underestimated during centrifugation of the diseased side. The posttreatment findings demonstrate that VEMPs were absent in all treated patients, and the caloric response was abnormally low in all but one case. In contrast, only 12 of 19 patients produced abnormal SVV responses. The results demonstrate that incremental, intratympanic application of gentamicin effectively eliminates semicircular canal and saccular function. In contrast, utricular function appears to be maintained in 30 to 40% of cases.

Intratympanic gentamicin in monolateral Meniere’s disease: our experience

The aim of this study was to verify the efficacy of a modified Odkvist titration protocol of intratympanic gentamicin application in the control of vertigo attacks and the effects on the auditory and vestibular function in a group of 71 patients affected by monolateral MD resistant to medical therapy. All the patients underwent an intratympanic administration of a 1-ml solution containing 26.6 mg of gentamicin sulfate. The treatment protocol provided one to three injections for a total amount of gentamicin varying from 26.6 to 80 mg. Five days after the first gentamicin administration, cochlear and vestibular function tests were performed. The worsening of the PTA greater than 15 dB, the appearance of clinical signs of vestibulotoxicity such as imbalance or persistent spontaneous nystagmus beating away from the injected ear or of a "curative vertigo" were the criteria taken into consideration to stop the treatment. In the absence of any sign, a second and third injection were performed. The presence of an unchanged frequency of the attacks at least 3 months after the previous cycle was the parameter considered to perform a second or third cycle. Seventeen (24%) patients were submitted to a second cycle of therapy and two (3%) to a third cycle. After a mean follow-up period of 20.3 months (range: 3 to 48) all 71 patients experienced good control of the vertigo attacks: grade A in 46 cases and grade B in 25 cases according to the AAO-HNS CoHE criteria. The pure tone average (PTA) hearing threshold (500-3,000 Hz) worsened in 19 patients, improved in 5 and was unchanged in 47. On the basis of the experience acquired during the treatment, we progressively decreased the number of injections from 3/cycle to a 1-2/cycle of therapy. Moreover, in the later phase of the study re-injections were administered 1 or 2 weeks after the previous application and avoided in the presence of signs of depression of the vestibular and/or cochlear function. A residual caloric excitability was found in 30% of the cases. Vertigo control doesn't seem to be linked to the achievement of vestibular inexcitability. The marker of successful gentamicin treatment at short-term is the appearance of signs of curative vertigo and/or vestibular imbalance, and at long-term the disappearance of vertigo attacks.

Treatment of Ménière's disease by intratympanic gentamicin application.

Ménière's disease is a vestibular disorder characterized by episodic vertigo, tinnitus, fluctuant hearing loss, and ear fullness, with vertiginous attacks being the most disabling complaint. The effectiveness of conservative treatment has been variable, while surgical techniques provide more permanent relief from vertigo, but pose possible morbidity and cochlear risk. Intratympanic administration of gentamicin has been proposed as an alternative for patients with debilitating Ménière's disease who have failed to respond to standard medical treatment. The goal of such treatment is to control vertigo by partially or completely destroying the vestibular system, while at the same time maintaining hearing. In this review we present the current medical literature on pathophysiology, pharmacokinetics, administration methods, dosage, treatment protocols, and problems related to intratympanic administration of gentamicin for patients with MD. Intratympanic gentamicin administration is a simple medical modality for treatment of persistent vertigo in patients with Ménière's disease. According to recent world research protocols, we propose the instillation of gentamicin by transtympanic injection, as a quick, easy, well-tolerated, ambulatory and cost-effective technique. Drug solution concentrations should be dependent on the frequency, intensity and duration of vertigo spells, as well as the degree of existing hearing loss, thus providing progressive vertigo relief with a low possibility of secondary deafness.

New possibilities in the treatment of Meniere's disease

The results of the treatment of Meniere's disease by intratympanic instillation of gentamicin in 32 patients over a 24-months period were analyzed. The receded vestibular function was found in 96.8% patients, whereas in the remaining 3.2% pronounced vestibular hypofunction was observed. One month after the treatment vertiginous attacks disappeared in all the patients. However, three months after the treatment infrequent episodes of mild degree vertigo and mild unsteadiness that did not require additional intratympanic gentamicin application appeared in 15% of the patients with Meniere's disease. The vertiginous attacks ceased or were pronouncedly reduced in 85% of the patients. The unstable vestibular hypofunction was successfully converted into stabilized, centrally compensated areflexia. Intratympanic gentamicin exerted better results than the other invasive therapies for intractable Meniere's disease.

Intratympanic application of gentamicin for treatment of Menière's disease.

Since 1974 we have treated 118 patients suffering from unilateral and bilateral (two patients) Morbus Meniere with intratympanal applications of gentamicin-sulfate. In contrast to earlier attempts using this method, we did not try to destroy the vestibular apparatus, but taking into our considerations the recent findings about the pathophysiological mechanism of Morbus Meniere, only to damage the secretory epithelium thus preventing the endolymphatic hydrops. Relief from symptoms could be obtained in more than 90% of our patients.