|Year : 2016 | Volume
| Issue : 2 | Page : 110-118
Low dose intratympanic gentamicin for control of intractable vertigo
H Gayathri1, Sutrave Satyananda Rao2
1 Department of ENT, A.C.S. Medical College and Hospital, Chennai, Tamil Nadu, India
2 Department of ENT, Vijayanagar Institute of Medical Sciences, Bellary, Karnataka, India
|Date of Web Publication||11-May-2016|
Department of ENT, A.C.S. Medical College, Velappanchavadi, Chennai, Tamilnadu
Source of Support: None, Conflict of Interest: None
Background and Objectives: Intratympanic gentamicin therapy is an effective modality for control of vertigo in Meniere's disease (MD) and when given in low concentration (<30 mg/mL), once weekly minimizes its side effects like chronic vestibular insufficiency or hearing loss. We studied the efficacy of low dose interval intratympanic gentamicin therapy in control of intractable vertigo in MD and the postprocedure hearing loss. As gentamicin is vestibular end-organ selective and not specific for treatment of MD alone we studied its efficacy in non-Meniere's peripheral vertigo (NMPV) in patients with nonserviceable hearing in affected ear. Subjects and Methods: Our study included 13 patients with “Definite” MD and seven patients with NMPV. In MD group, one treatment series consisted of a maximum of 3 weekly intratympanic gentamicin injections of 0.3 mL (12 mg) of gentamicin. In NMPV group, the schedule was similar but dosage per injection was 0.5 mL (20 mg). Another similar series of injections were repeated for recurrences. Results: Significant reduction was noted in number of vertigo spells in both groups after treatment (P < 0.001). All the patients experienced either complete or substantial control (Class A or B) of their vertigo. The functional level scale had significantly improved posttreatment in both groups (P < 0.01). No significant worsening in hearing was noted in any of the patients in MD group. Interpretation and Conclusion: Low dose interval intratympanic gentamicin is a simple cost-effective office procedure for managing vertigo in patients with MD and in patients with NMPV and nonserviceable hearing.
Keywords: Gentamicin, Hearing loss, Meniere's disease, Vertigo
|How to cite this article:|
Gayathri H, Rao SS. Low dose intratympanic gentamicin for control of intractable vertigo. Indian J Otol 2016;22:110-8
| Introduction|| |
Meniere's disease (MD) was first described by Dr. Prosper Meniere in 1861 as a disorder characterized by episodic vertigo, fluctuant hearing loss, tinnitus and ear fullness with vertiginous attacks being the most disabling symptom. Exact etiology of the disease is not known though the most popular theory reaffirms endolymphatic hydrops as the underlying pathology. In most of the cases etiology of hydrops is unknown (primary endolymphatic hydrops) whereas in few cases specific causes are identified (secondary endolymphatic hydrops) like developmental anomalies, hypo or hyperglycemia, hyperlipidemia, hypo or hyperthyroidism, adrenocorticotrophic hormone deficiency, syphilis, trauma, chronic suppurative otitis media, autoimmune inner ear disease, delayed endolymphatic hydrops after old sensorineural hearing loss (SNHL).
Other common causes of peripheral vertigo are benign paroxysmal positional vertigo (BPPV), labyrinthitis, vestibular neuronitis, trauma, vascular disease involving anterior inferior cerebellar artery or internal auditory artery, vestibular paroxysmia, vestibular schwannoma and other CP angle tumors.
In progressive MD, despite medical treatment, the symptoms worsen and often become incapacitating and intractable. These patients (estimated as one out of four) are candidates for surgery and the rest can be successfully managed with medical treatment.
The physiologic rationale for surgical vestibular ablation is based on the fact that compensation for peripheral vestibular dysfunction seems to be more rapid when unilateral vestibular dysfunction is fixed rather than fluctuating and the absence of unilateral peripheral input to vestibular stimuli is more easily compensated, compared with disordered vestibular input.
Labyrinthectomy is indicated in cases with disabling peripheral vertigo who have not responded to a substantial trial of medical line of management and who have severe hearing loss but it creates a dead labyrinth, has possibility of complications like facial nerve injury, potential cerebrospinal fluid (CSF) leak, and prolonged central compensation.
Patients who have serviceable hearing, can opt for selective vestibular neurectomy. But the procedure demands for intensive care in postoperative period in view of its intracranial nature and can be complicated by CSF leak, facial palsy, injury to sigmoid sinus, other lower cranial nerves, cerebellum, labyrinthine artery and cerebral edema.
Endolymphatic sac surgery, though is logically sound for treating MD and is associated with preservation of hearing comparable to vestibular neurectomy, and can be performed even bilaterally without significant postprocedure chronic vestibular insufficiency, has shown inconsistent results at time not better than a placebo.
Intratympanic gentamicin therapy is a relatively easy procedure to perform, accomplished in the office environment, is inexpensive, and usually is not disabling and achieves good control of vertigo. The potential complications of intratympanic gentamicin include hearing loss, tympanic membrane perforation, irritative spontaneous nystagmus, and a temporary acute unilateral vestibular deafferentation syndrome involving vertigo, nausea, oscillopsia, and dysequilibrium.
There is no general agreement on the optimal concentration, temporal sequence, or total dose of intratympanic gentamicin. The reported experience with intratympanic gentamicin indicates that 1 injection per week (1–2 mL with concentrations <30 mg/mL) on an outpatient basis can be recommended to better monitor the delayed ototoxic effects like hearing loss and vestibular insufficiency.
Hence in this study, we attempt to test the efficacy of low dose interval intratympanic gentamicin for the control of vertigo in MD and to monitor the postprocedure hearing loss.
As intratympanic gentamicin therapy is not disease specific, but rather pathophysiology specific any disease process which as an end result develops vertigo secondary to end-organ disease is amenable to intratympanic gentamicin ablative therapy.
Hence in this study we attempt to expand the indications for intratympanic gentamicin in other causes of peripheral vertigo other than MD. But as not many studies have been published in this regard, we are only studying the efficacy of the treatment in patients with nonserviceable hearing in this group.
| Subjects and Methods|| |
Ours was a prospective clinical study done on twenty patients with intractable peripheral vertigo - 13 patients with “Definite” (MD Group) and seven patients with non-Meniere's peripheral vertigo (NMPV group) with severe to profound hearing loss in the affected ear.
Data was collected from patients in a specially designed case record form by taking detailed history, performing relevant examination and investigations.
Pretreatment evaluation included complete ontological, cardiovascular, ophthalmological and cervical spine examination; pure tone audiogram with speech discrimination score (SDS), glycerol test, electronystagmography with caloric test. Brain stem evoked response audiometry was done in all cases of suspected MD. Magnetic resonance imaging (MRI) with gadolinium contrast was done in all cases of NMPV to rule out any retrocochlear pathology.
Additional investigations were done to rule out secondary endolymphatic hydrops like fluoroscent treponemal antibody test for syphilis, antinuclear antibody for autoimmune disorders, serum electrolytes for electrolyte disturbance, fasting blood sugar, thyroid profile and lipid profile for any derangement.
Patient inclusion criteria
- Cases of definite MD according to AAO-HNS CoHE 1995 guidelines 
- Cases of non-Meniere's intractable peripheral vertigo with severe to profound SNHL in affected ear
- With serviceable hearing in other ear (i.e., Speech reception threshold (SRT) <50 dB, SDS >50% in the other ear).
- Cases of central vertigo
- Cases of peripheral vertigo other than MD with serviceable hearing in affected ear
- Cases of secondary endolymphatic hydrops when primary cause hasn't been treated.
Intratympanic gentamicin was administered as an outpatient procedure. The patient was made to lie in supine position with the affected ear upwards facing the otomicroscope, after placing 4% lignocaine cottonoids for 10 min over tympanic membrane, 0.3 mL of 40 mg/mL nonbuffered gentamicin solution was taken in an insulin syringe with 1.5-inch long 26 gauge needle and injected through postero-inferior quadrant of the tympanic membrane till middle ear is completely filled and tympanic membrane was seen bulging [Figure 1]. The patient remains in the same position for half an hour and is told to avoid any swallowing movements during this period. Patient is also instructed to keep the ear dry for 2 weeks. The same was repeated weekly for a maximum of 3 doses. The primary schedule was terminated earlier if signs of vestibular deafferentation like spontaneous nystagmus or positive head shake nystagmus or head thrust sign appeared or patient reported control of vertigo or developed disequilibrium. In case of any recurrence the same schedule was followed. The patients in NMPV group received a higher dose 20 mg (0.5 mL) of the solution per sitting, rest of the schedule was similar to MD group.
|Figure 1: Left sided intratympanic gentamicin being administered with insulin syringe with 26 gauge 1.5-inch long needle, site of injection-posteroinferior quadrant|
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All the patients were followed up for a period of 6 months after their primary schedule.
Control of vertigo was assessed by the numerical value of:
Class of control reported based on AAO-HNS CoHE guidelines. Disability level was assessed pre- and post-treatment based on functional level scale (FLS) during and between attacks.
Pre- and post-treatment pure tone average (PTA) (0.5, 1, 2, 3 kHz) along with SDS were compared. A change of more than 10 dB in PTA or >15% in SDS was considered significant. If patient developed any hearing loss, that was informed to the patient and further dosing was left to the choice of the patient.
Paired t-test has been used to find the significance of study parameters on continuous scale within each group and Wilcoxon matched pairs test has been used to find the significance of discrete variable on nonparametric condition and Chi-square test has been applied for comparison of results between two groups. The statistical software namely SPSS 15.0, STATA 8.0, Medcalc 9.0.1, Systat 11.0 were used for analysis of the data.
| Results|| |
Group 1: Meniere's disease group
The demographic data, caloric test response, glycerol test response, pre- and post-injection PTA Air conduction and Bone conduction (AC and BC), SDS%, FLS, number of vertigo spells and class of control are mentioned in [Table 1].
The number of injections given in primary schedule varied from 1 to 3 with 10 out of 13 patients (76.9%) needing all 3 doses. Most of the patients (76.9%) didn't have any recurrences during the 6 months of follow-up. Only three patients had experienced episodes of definitive vertigo which they experienced after 2 months time who were given second series of injections. Significant reduction (P < 0.0001) was noted in number of vertigo spells postinjection (96.6%) [Table 2].
|Table 2: Change in number of vertigo spells following treatment in Meniere's disease group|
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Out of the three patients having recurrences, two patients developed signs of unilateral vestibular dysfunction by 2nd injection and the third patient needed 3 doses for the same. Patients were symptom free since the second schedule for the next 4 months. Hence, on an average a total dose of 39.8 mg (range - 12–72 mg) of intratympanic gentamicin was required for control of vertigo.
All patients achieved either Class A or Class B control. Class A was more common than Class B (76.9% vs. 23.1%) in MD group. The postinjection FLS had significantly improved (P = 0.001) postinjection when compared to preinjection phase (1 vs. 4) [Table 3].
|Table 3: Pre- and post-injection functional level scale in Meniere's disease group|
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Significant worsening wasn't noted in any of the patients. Most common observation was insignificant improvement which was seen in seven patients (53.8%) (P = 0.01) [Table 4].
SDS was unchanged in 12 of 13 patients. (92.3%), only one patient had shown insignificant worsening (7.7%) (P = 0.337).
Group 2: Non-Meniere's peripheral vertigo group – observations and results
The demographic data, diagnosis, caloric test response, glycerol test response, pre- and post-injection PTA (AC and BC), SDS%, FLS, number of vertigo spells and class of control are mentioned in [Table 5].
The number of injections given in primary schedule varied from 2 to 3 with 6 out of seven patients (85.7%) needing all 3 doses. Three (42.9%) patients didn't have any recurrences during the 6 months of follow-up. Among the rest, three patients (42.9%) had experienced 2 episodes of vertigo and one patient (14.3%) had 3 episodes of vertigo which they experienced after 2–3 months time. Significant reduction (P < 0.001) was noted in number of vertigo spells postinjection (90.1%) [Table 6].
|Table 6: Change in number of vertigo spells following treatment in non-Meniere's peripheral vertigo group|
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Out of the four patients having recurrences, two patients developed signs of unilateral vestibular dysfunction by 2nd injection and the other two patients needed 3 doses for the same. Patients were symptom free since the second schedule for rest of follow-up period. Hence, on an average a total dose of 80 mg (range - 40–120 mg) of intratympanic gentamicin was required for control of vertigo.
All patients achieved either Class A or Class B control. Class B was more common than Class A (57.1% vs. 42.9%) in NMPV group. The postinjection FLS had significantly improved (P < 0.001) postinjection when compared to preinjection phase (1 vs. 3) [Table 7].
|Table 7: Pre- - and post-injection functional level scale in non-Meniere's peripheral vertigo group|
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Most of the patients (85.7%) had profound hearing loss even prior to injection. The preinjection average of bone conduction for frequencies - 0.5, 1, 2, 3 kHz varied 68.75–85 dB with majority in the range of 71–90 dB (85.7%).
Comparison between two groups
Class of control A type was more prevalent in MD group while B class of control was prevalent in NMPV group though not with a significant difference (P = 0.152) [Table 8].
Total dose required was significantly less (39.79 mg vs. 80.00 mg) in MD group when compared to NMPV group [Table 9].
| Discussion|| |
According to the current medical literature, intratympanic gentamicin therapy has emerged as a standard mode of therapy to decrease vertigo associated with MD. Most studies have achieved control of vertigo in more than 85% of patients treated with intratympanic gentamicin, whatever protocol or technique they used. Varying regimens have been used for intatympanic gentamicin therapy. The trend is changing from high dose to low dose and from fixed dosage with multiple doses per day to daily dosage towards titrated dosage administered once in a week and finally single shot therapy. However, the ongoing debate for optimal dose continues with doses of 39–600 mg have been reported.
Gentamicin binds with Na +-K +–adenosine triphosphatase of the specialized secretory dark cells of vestibular labyrinth that are involved in endolymph production. This first step is reversible on suspending administration of the drug and results in reduced endolymph production and subsequent control of vertigo spells. A second irreversible stage seems to be mediated by the disruption of mitochondrial protein synthesis, the overactivation of glutaminergic receptors and the formation of free radicals, cellular calcium influx and calpain activation. Recent data explain the use of reduced doses and frequency of gentamicin administration to prevent irreversible toxicity of hair cells, as cochlear damage is dose related. It is also evident that complete ablation of the vestibular function is not necessary to obtain total control of vertigo. However hair cell damage does occur and the initial and most extensive one occurs in the apex of the cristae and the striolae of maculae, and then progress to periphery and involve otoconial membrane and otolith structures as well.
Once aminoglycosides reach the endolymph, these drugs are selectively concentrated in hair cells as well as in support cells. through the cation channels by endocytosis, in which these drugs are actively internalized in vesicles and transferred to the lysosomes, where due to action of lysosomal enzymes vesicles swell and rupture. This delayed exposure of targets of action in the cytoplasm or nucleus to the drug may be responsible for the delay often seen between gentamicin treatment and the onset of symptoms of vestibular hypofunction. Drugs enter perilymph relatively slowly and reach peak concentration at approximately 4 h. The half-life time of aminoglycosides in the inner ear fluids has been shown to be more than 30 days, and traces of aminoglycosides in the hair cells were found as long as 11 months after treatment.,
Slow destruction of the vestibular end-organ with intratympanic gentamicin, in contrast to the immediate destruction with labyrinthectomy or nerve section, may also allow the central vestibular system to compensate more effectively.
In our study, we followed a protocol similar to Lange et al. study  using low dose intratympanic injection of gentamicin 12 mg/dose (0.3 mL of the solution) with interval therapy, successive doses given in a week gap. Maximum of 3 doses were given in the primary schedule, the series was ended earlier if patient developed curative vertigo or significant hearing loss or signs of vestibular deafferentation. The series was repeated in same dosage for recurrence. Re-injections aren't given earlier than 7 days after preceding application as this avoids over intoxicaton and potential cochleotoxic side effects. In our study in MD group, the number of the injections given in primary schedule varied from 1 to 3 with 10 of 13 patients needing all 3 doses.
As per AAO-HNS CoHE guidelines  patients have to be monitored for a minimum of 2-year period prior to reporting results of study. Due to time constraints for our study, only 6 months follow-up after primary schedule or first series was feasible.
In a study by Driscoll et al., a single dose of gentamicin (10–80 mg) was injected into the middle ear space of 23 patients with unilateral MD. Eighty-four percent of patients had no episodes of vertigo in 6 months follow-up time. PTA and SDS were not affected significantly.
In a recent prospective study by Daneshi et al., thirty patients with unilateral MD were treated with one shot intratympanic injection of 20 mg of gentamicin. Mean vertigo attacks frequency, PTA threshold and FLS significantly decreased after the treatment (P < 0.05). Class A control was attained in 58.3% and Class B control in 37.5% of the patients.
In the study by Lange et al., ninety patients were treated with the single-shot or interval gentamicin therapy. Thirty of these 57 patients (53%) needed only one injection to be controlled (single shot treatment). Vertigo attacks were completely controlled in 95% and partially controlled in 5%, whereas hearing remained unchanged or even improved. Tinnitus as well as aural fullness was controlled in approximately 50% of the cases. PTA was mostly unaffected but 7% of patients had significant improvement and 9% had 10–15 dB hearing loss.
Similar to other studies with low dose intratympanic gentamicin, significant reduction (P = 0.0001) was noted (0.46 vs. 13.84) in number of vertigo spells postinjection (96.6%) in MD group in our study. All patients in MD group achieved either Class A or Class B control. Class A was more common than Class B (76.9 vs. 23.1%). The FLS in MD group had significantly improved (P = 0.001) postinjection when compared to preinjection phase (1 vs. 4). Even the recurrent episodes were of lesser severity and duration when compared to the pretreatment ones.
Most common observation seen in posttreatment audiogram in MD group was insignificant improvement which was seen in seven patients (53.8%). SDS remained unchanged in 12 patients (92.3%). Significant worsening in PTA or SDS wasn't noted in any of the patients in our MD group similar to Lange's study.
Application of intratympanic gentamicin has been largely restricted to cases to unilateral MD with nonserviceable hearing. As low dose intratympanic gentamicin offers quite good control of vertigo without causing substantial hearing loss it can be applied even in cases with serviceable hearing in affected ear or bilateral MD as in our study.
As action of gentamicin isn't pathology specific but specific to vestibular end-organ, the indication for intratympanic gentamicin can be broadened to include even other causes of peripheral vertigo as done by Brantberg et al. and P. W. Bauer  Brantberg et al. had reported successful control of vertigo in five cases of peripheral vertigo other than MD like intractable BPPV, acoustic neuroma in an old patient and in patients with vertigo and deaf ear. Bauer et al. presented a series of six patients with successful control of vertigo that was caused by end-organ disease, in an ear without serviceable hearing. Two patients suffered from delayed endolymphatic hydrops, 3 from MD, and 1 from poststapedectomy vertigo.
In our study we had seven patients enrolled in NMPV group with nonserviceable hearing (<50 dB SRT or <50% SDS), of which five patients had delayed endolymphatic hydrops. Of these, two patients had developed sudden SNHL 2 years prior to onset of vertigo, one patient had history of traumatic hearing loss secondary to temporal bone fracture - 5 years before onset of vertigo, one patient had SNHL secondary to suppurative labyrinthitis - 2 years prior to onset of vertigo and the last patient had inactive chronic otitis media of tubotympanic type with negative fistula test with SNHL since 20 years and had lost his hearing during the first episode of ear discharge. One patient (14.3%) had history similar to MD with left chronic suppurative otitis media of tubotympanic type with negative fistula test, which didn't improve even after surgery (simple mastoidectomy with type I tympanoplasty) and hence was diagnosed to have secondary endolymphatic hydrops. One patient (14.3%) had history of left temporal bone fracture 2 years back following which had hard of hearing and on and off attacks of vertigo since the time of injury. All the patients had an MRI with gadolinium contrast done that was negative for any retrocochlear organic pathology.
The technique of injection was similar to MD group in most of the patients except the case who had chronic suppurative otitis media for whom the same solution was instilled through the perforation. The dose per application was higher (20 mg) than that used for MD group. The comparatively higher dose was used as the patients already had severe to profound hearing loss. Unlike our regimen, Paul Kasperbauer et al. had used 0.5–1 mL of 30 mg/mL per dose for up to 6 doses, with the doses being repeated every other day.
Significant reduction (P < 0.001) was noted in number of vertigo spells postinjection (90.1%) in NMPV group as well. The postinjection FLS had significantly improved (P = 0.014) postinjection when compared to preinjection phase (1 vs. 3) even in NMPV group. All patients achieved either Class A or Class B control. Class B was more common than Class A (57.1 vs. 42.9%) in NMPV group.
None of the patients in both groups had permanent perforation (secondary to injection) or long term disequilibrium following our treatment.
In this study, the patient sample size is small and follow-up is short; but still the results of the study should motivate expansion of indication of intratympanic gentamicin therapy even in NMPV with serviceable hearing as well.
We wish to thank the other senior faculty members and postgraduates and audiologist in the Department of Otorhinolaryngology, VIMS Bellary for their kind support. We would also like to wish Dr. P. Rathnasamy and Dr. K. Balachandran, Professors in Department of Otorhinolaryngology at A. C. S. Medical College for their due help in reviewing this article and Dr. Saranya Nagalingam, A. C. S. Medical College for helping with the statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Moffat DA, Ballagh RH. Ménière's disease. In: Scott-Brown's Otolaryngology, 6th
edition, Vol. 3, Chapter 19, editor Booth JB. Oxford: ButterworthHeinemann; 1997. p. 1-50.
Paparella MM. The natural course of Meniere's disease. In: Filipo R, Barbara M, editors. Proceedings of the Third International Symposium on Meniere's Disease. Amsterdam: Kugler; 1994. p. 9-20.
Nadol JB, McKenna MJ. Labyrinthectomy. In: Nadol JB, editor. Surgery of the Ear and Temporal Bone. 2nd
ed. Philadelphia, U.S.A.: Lippincott Williams and Wilkins; 2005. p. 367-74.
Berryhill WE, Graham MD. Chemical and physical labyrinthectomy for Meniere's disease. Otolaryngol Clin North Am 2002;35:675-82.
Nadol JB, McKenna MJ. Neurectomy procedures for vertigo. In: Nadol JB, editor. Surgery of the Ear and Temporal Bone. 2nd
ed. Philadelphia, U.S.A.: Lippincott Williams and Wilkins; 2005. p. 381-90.
Thomsen J, Bretlau P, Tos M, Johnsen NJ. Placebo effect in surgery for Meniere's disease: Three-year follow-up. Otolaryngol Head Neck Surg 1983;91:183-6.
Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Menière's disease. Acta Otolaryngol (Stockh) 1991;111:671-6.
Bauer PW, MacDonald CB, Cox LC. Intratympanic gentamicin therapy for vertigo in nonserviceable ears. Am J Otolaryngol 2001;22:111-5.
Monsell EM, Balkany TA, Gates GA, Goldenberg RA, Meyerhoff WL, House JW. Committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease. Otolaryngol Head Neck Surg 1995;113:181-5.
Daneshi A, Jahandideh H, Pousti SB, Mohammadi S. One-shot, low-dosage intratympanic gentamicin for Ménière's disease: Clinical, posturographic and vestibular test findings. Iran J Neurol 2014;13:33-9.
Rodriguez V, Perez-Garrigues H, Morera C. Evaluation of 2 procedures of intratympanic gentamicin therapy in Meniere's disease. Int Adv Otol 2013;9:82-8.
Tran Ba Huy P, Bernard P, Schacht J. Kinetics of gentamicin uptake and release in the rat. Comparison of inner ear tissues and fluids with other organs. J Clin Invest 1986;77:1492-500.
Carey J. Intratympanic gentamicin for the treatment of Meniere's disease and other forms of peripheral vertigo. Otolaryngol Clin North Am 2004;37:1075-90.
Lange G, Maurer J, Mann W. Long-term results after interval therapy with intratympanic gentamicin for Menière's disease. Laryngoscope 2004;114:102-5.
Driscoll CL, Kasperbauer JL, Facer GW, Harner SG, Beatty CW. Low-dose intratympanic gentamicin and the treatment of Meniere's disease: Preliminary results. Laryngoscope 1997;107:83-9.
Brantberg K, Bergenius J, Tribukait A. Gentamicin treatment in peripheral vestibular disorders other than Ménière's disease. ORL J Otorhinolaryngol Relat Spec 1996;58:277-9.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]