Intratympanic Gentamicin Therapy for Vertigo in Nonserviceable Ears

Intratympanic Gentamicin Therapy for Vertigo in Nonserviceable Ears Paul W. Bauer, MD, C. Bruce MacDonald, MD, and L. Clarke Cox, PhD Purpose: Intratympanic ototoxic agents have become a widely accepted means of managing vertigo in patients with Meniere s disease while preserving residual hearing. We investigated expanding the indications for intratympanic gentamicin to include control of vertigo in patients without serviceable hearing in the involved ear caused by a variety of end-organ pathologies. Materials and Methods: We present a retrospective series of 6 patients suffering from vertigo caused by end-organ disease, in an ear without serviceable hearing. Two patients suffered from delayed endolymphatic hydrops, 3from Meniere s disease, and 1 from poststapedectomy vertigo. These patients chose unilateral vestibular ablation with serial intratympanic gentamicin injection rather than labyrinthectomy for a variety of reasons. Conventional electronystagmography (ENG) testing and audiometry were completed on all patients. The ENG testing included bithermal calorics and rotational testing. All patients had a magnetic resonance image with gadolinium to exclude retrocochlear or central pathology. Rotational testing was repeated before each injection and at the conclusion of therapy to assess changes in the peripheral vestibular response. The patients subjective response to therapy was followed. Results: Follow-up has been 10 to 69 months with successful control of vertigo in all patients. Conclusions: Intratympanic gentamicin therapy offers a minimally invasive, ambulatory, low morbidity, cost-effective means of managing vertigo in patients with nonserviceable hearing. (Am J Otolaryngol 2001;22:111-115. Copyright 2001 by W.B. Saunders Company) The use of intratympanic aminoglycosides to pharmacologically ablate the vestibular system in cases of intractable vertigo was introduced by Schuknecht in 1957. He administered high doses of intratympanic streptomycin and found that ablation of the ice water caloric response was necessary to control vertigo. Unfortunately, of the 8 patients treated, all had complete loss of hearing. Schuknecht 1 concluded that vestibular function cannot be destroyed with intratympanic streptomycin without compromising hearing in the treated ear. Intratympanic aminoglycosides were reintroduced to the English literature by Beck and Schmidt 2 in 1978. They recognized that total vestibular end-organ destruction was not From the Department of Otolaryngology-Head and Neck Surgery, Boston University School of Medicine, Boston, MA. Address reprint requests to L. Clarke Cox, PhD, Department of Otolaryngology-Head and Neck Surgery, Boston Medical Center-D616, 88 East Newton Street, Boston, MA 02118-2393. Copyright 2001 by W.B. Saunders Company 0196-0709/01/2202-0004$35.00/0 doi:10.1053/ajot.2001.22569 needed to control vertigo. They advocated the use of gentamicin, as toxic effects in the secretory dark cells precede changes in the vestibular sensory neuroepithelium. Hearing loss occurred in only 15% of their 40 patients. Intratympanic gentamicin has become a widely accepted hearing conservation therapy for vertigo in Meniere s disease. Recent literature reports success in controlling vertigo in the range of 77% to 95% and unchanged or improved hearing in 62% to 80% of patients. 3-6 The range of these results appears to be related to variations in dosing regimens and the concentration of gentamicin. This literature supports the use of intratympanic gentamicin in patients with Meniere s disease who have serviceable hearing and were therefore not candidates for labyrinthectomy. In fact, a careful review of the data reveals that several studies have included some patients with nonserviceable hearing in the involved ear. 3,4,6,7 In addition, Brantberg et al 8 recently suggested expanding the indication for intratympanic gentamicin to include patients suffering from vertigo with a diagnosis other than Meniere s disease. American Journal of Otolaryngology, Vol 22, No 2 (March-April), 2001: pp 111-115 111

112 BAUER ET AL This article reports our experience in expanding the indications for intratympanic gentamicin to include control of vertigo in patients without serviceable hearing in the involved ear, caused by a variety of end-organ pathology. MATERIALS AND METHODS Data are presented on 6 patients with episodic vertigo managed with intratympanic gentamicin. Patient 1 is a 66-year-old man who had reported episodic vertigo, right aural fullness, and tinnitus for the past 30 years. After presenting to our clinic, he was managed with dietary restrictions and hydrochlorothiazide 25 mg/triamterene 37.5 mg daily for 12 months. At that point, he suffered on two occasions an otolithic crisis of Tumarkin. Patient 2 is a 52-year-old woman who originally presented with fluctuating hearing loss and acute onset of whirling vertigo. She was subsequently managed with dietary restrictions, hydrochlorothiazide 25 mg/triamterene 37.5 mg daily, and meclizine as needed for 18 months. Initially, she responded well to therapy; however, over the past 6 months she reported brief episodes of severe vertigo, fluctuating hearing loss, and left tinnitus. Patient 3 is a 48-year-old man in whom during a stapedectomy for otosclerosis the footplate apparently fell into the labyrinth and was not retrieved. He initially had good hearing as a result of his surgery. He reported complaints of slowly progressive hearing loss on the right and intermittent episodes of whirling vertigo 5.5 years after surgery. At the time an audiogram revealed a bilateral, mild, low-frequency sensorineural hearing loss (SNHL) and a right, sloping, high frequency ( 2,000 Hz) SNHL. The patient returned again 3.5 years later, now reporting that his right hearing aid no longer functioned and that his whirling vertigo now occurred more frequently. His vertigo involved transient, severe dizziness and imbalance that was quite unpredictable, not related to movement, and lasted for approximately 2 minutes. An audiogram on the left revealed a progression of his low-frequency SNHL and no response on the right. Patient 4 is a 74-year-old man who had been diagnosed with a profound, right, unilateral SNHL many years ago. He reported complaints of a several-month history of rotatory vertigo with nausea and vomiting. He was 6 months out from surgery and radiation therapy for gastric adenocarcinoma. Patient 5 is an 81-year-old man who presented with a severaldecade history of intermittent episodes of whirling vertigo, nausea, and vomiting, associated with roaring tinnitus lasting most of the day and a progressive right hearing loss. The vertigo had been managed with dietary restrictions and meclizine as needed. The patient had fallen and injured himself during a recent episode of vertigo. Patient 6 is a 42-year-old man who reported a complete loss of hearing in his left ear 25 years ago and a 5-year history of episodic vertigo and left-sided tinnitus. His vertigo had been managed with hydrochlorothiazide 25 mg/triamterene 37.5 mg daily and meclizine. Delayed endolymphatic hydrops is defined as profound unilateral or bilateral SNHL incidentally discovered in childhood or related to some specific disease process or trauma and the subsequent delayed onset of episodic vertigo. 9 Patients with Meniere s disease were diagnosed according to standard criteria. 10 The demographics of the patients with their pretherapy audiometry are summarized in Table 1. Serviceable hearing in unilateral disease was defined as a speech reception threshold of less than 50 db and a word discrimination score of more than 50%. Audiometric measurements below these were considered to represent nonserviceable hearing. Before initiating therapy, all patients underwent an initial vestibular testing battery and audiometry. The battery included conventional ENG with bithermal calorics and assessment of the vestibular ocular reflex (VOR) with rotational testing. The TABLE 1. Data From Six Patients Treated Intratympanically with Gentamicin Pt. No. Age and Gender Diagnosis Side Treated Follow-up (mos) Speech Reception Threshold (db) Word Recognition Score (%) Pure Tone Average (db) L R L R L R 1 66M MD R 69 30 60 96 44 36 64 2 52 F MD L 50 65 5 28 100 72 15 3 48M PSV R 37 25 NR** 100 CNT*** 35 120 4 74M DEH R 10 20 90 96 12 22 83 5 81M MD R 28 30 105 100 CNT 35 85 6 42M DEH L 26 NR 15 CNT 96 120 13 Abbreviations: DEH, delayed endolymphatic hydrops; MD, Meniere s disease; PSV, poststapedectomy vertigo; NR, no response; CNT, could not test.

GENTAMICIN THERAPY IN NONSERVICEABLE EARS 113 VOR test consisted of patient rotation around a vertical axis from 0.01 to 0.64 Hz. All patients had a magnetic resonance image with gadolinium to exclude retrocochlear or central pathology before initiating destructive, chemical ablation of the vestibular end organ. Patients were given the option of gentamicin therapy or transmastoid labyrinthectomy. These patients chose gentamicin for various reasons: Patient 1 secondary to a cardiac arrhythmia: patient 3 because of severe obstructive sleep apnea which both had a high anesthesia risk; patient 4 had inoperable gastric carcinoma and wished to avoid surgery; patient 5 was not interested in pursuing any surgical option because of his advanced age; and patients 2 and 6 were surgical candidates who chose to pursue nonsurgical therapy to avoid taking time off work. The concentration of gentamicin was 30 mg/ml in a solution buffered to a ph of 6.5. Topical phenol was used for local anesthesia before injection, with subsequent injections the hole was often still present and phenol was not needed. A total of 0.5 to 1.0 ml was injected into the middle ear space using a 25-gauge needle every other day for a total of 6 doses. After injection, the patients were asked to lay supine for 30 minutes. Patients who required repeat injections followed the same protocol but received only 3 injections. RESULTS Four patients have reported a complete resolution of their episodic vertigo during the follow-up period of 10 to 69 months. Patient 1 had a recurrence of symptoms 26 months after therapy and opted for further injections. After 3 injections, he has remained free of symptoms for 43 months. Patient 3 had a recurrence of symptoms 30 months after therapy and opted for further injections. After 3 injections, he has remained free of symptoms for 8 months. Patient 4 died from gastric carcinoma 10 months after his injections; however, he remained free of symptoms during this time. All patients have reported residual mild dysequilibrium that does not limit their normal daily activity. None of the patients required a formal vestibular rehabilitation program to achieve these results. A review of patient rotational test data revealed a change in gain after the first injection for all patients. In general, complaints of vestibular symptoms, including dysequilibrium, nausea, and vomiting were noted after the initial injection. Complaints subsided with subsequent injections. Follow-up rotary testing documented recovery of the VOR gain after treatment to approximately the baseline. DISCUSSION All of the patients in the present study had nonserviceable hearing in the involved ear. Contralateral hearing ranged from normal to mild hearing loss (Table 1). When presented with these patients in the setting of vertigo refractory to medical management, the gold standard has been destructive surgical intervention. Recent reports of a large series of patients continue to recommend labyrinthectomy to their patients with coexisting episodic vertigo and nonserviceable hearing to destroy the vestibular sensory end organ and to relieve their symptoms. 11-13 Although the definition of nonserviceable hearing is controversial in patients with bilateral SNHL of more than 50 db, attempts would certainly be made to aid the patient s hearing. In this study, the patients all had unilateral disease with adequate hearing in the contralateral ear. Future advances in digital and biomedical technology may redefine the concept of nonserviceable hearing. Regardless, intratympanic gentamicin can continue to spare residual cochlear function while providing effective vestibular ablation. 2-7 Two of our patients were diagnosed with delayed endolymphatic hydrops. Other investigators advocate transmastoid labyrinthectomy or translabyrinthine cochleovestibular neurectomy for delayed endolymphatic hydrops which is refractory to traditional medical management. 9,13,14 A recent report describes the use of intratympanic gentamicin to treat vertigo in 5 patients with peripheral vestibular disorders other than Meniere s disease. 8 The detailed case descriptions for 3 of these patients is highly characteristic of delayed endolymphatic hydrops and is the first report of intratympanic gentamicin being utilized for a process other than Meniere s disease. Our study represents a group of patients treated with intratympanic gentamicin who had nonserviceable hearing in the involved ear. Of these, 3 had a diagnosis other than Meniere s disease. In this way, the data have the inherent bias of representing a select

114 BAUER ET AL group of patients and not all of the patients treated with intratympanic gentamicin at our institution. It does show the potential for expanding the indications for its use. Intratympanic gentamicin therapy is not disease specific, but rather is pathophysiology specific. Any disease process that, as an end result, develops vertigo secondary to end-organ disease is amenable to intratympanic gentamicin ablative therapy. The clinical characteristic of delayed endolymphatic hydrops that distinguishes it from Meniere s disease is that it occurs in patients with preexisting audiometric pathology. A delay of months to years usually occurs between the original insult and the development of hydrops. This finding is in contrast to Meniere s disease, in which hydrops occurs in patients with previously normal audiometric studies. Therefore, intratympanic gentamicin therapy should be effective in managing the symptoms of vertigo in patients with delayed endolymphatic hydrops, as the underlying etiology has been theorized to be secondary to either a damaged endolymphatic sac or a blocked vestibular aqueduct. Both etiologies would limit the reabsorption of endolymph and produce hydrops. In the patient with poststapedectomy vertigo, symptoms may represent an iatrogenic case of delayed endolymphatic hydrops. Advocates of labyrinthectomy in managing hydrops report complete relief or significant improvement of vertigo at a rate of 95% to 99%. 11,12,14 Patients with an uneventful postoperative course can expect a hospital stay of 2 to 4 days, with return to work in 3 to 4 weeks. 12,14 Although rare, the potential complications of a labyrinthectomy, include wound infections, postoperative dysequilibrium, minor taste abnormalities, facial nerve paralysis, cerebrospinal fluid leak, epidural hematoma, meningitis, and death. 11,13,14 This can be compared with intratympanic gentamicin therapy in managing vertigo, reporting complete relief or significant improvement at a rate of 84% to 95%. 3,4,6,7 Injections are completed on an outpatient basis, and patients generally will miss 2 or 3 days of work at the peak of postinjection dysequilibrium. 6 The potential complications of intratympanic gentamicin include hearing loss, tympanic membrane perforation, irritative spontaneous nystagmus, 15 and a temporary acute unilateral vestibular deafferentation syndrome involving vertigo, nausea, oscillopsia, and dysequilibrium. 5 Both labyrinthectomy and intratympanic gentamicin can be complicated by prolonged or permanent dysequilibrium. In our patient population with nonserviceable hearing, hearing loss would not be considered a complication and is the reason that hearing preservation surgical techniques are not discussed. It should be noted, however, that in the 2 patients with measurable speech scores no reduction was seen with treatment. This comparison has lead us to advocate the addition of intratympanic gentamicin therapy as the end point of all medical regimens before pursuing destructive surgical intervention, regardless of hearing level. The time course of our patients central compensation seems relatively short. Clinically, minimal vestibular morbidity was seen, patients had minimal disruption of their daily activities, and if they worked they were able to return to work the day after their injection. Initial VOR changes after the first injection returned to baseline during the course of therapy. Cass et al 16 reported complete compensation in 4 of their 20 patients by 7 days after vestibular nerve section. Li et al 17 reported that the compensation period following unilateral vestibular deafferentation was on average most notable by 2.6 months postoperatively. Patients appear to compensate relatively fast following gentamicin therapy. Three theoretical options are available. First, low residual function in the treated ear, as previously stated, may have allowed for significant central compensation to occur before initiating therapy. Second, the gentamicin has selective functions on the vestibular system. It was shown in an animal model that neurotoxic changes from intratympanic gentamicin affects changes in the dark cells before alterations in the sensory neuroepithelium. 18 There is histologic evidence that dark cells in the sensory epithelium of the labyrinth regulate the ionic content of endolymph. 19 The popular theory is that damage to the dark cells affects the production of endolymph, and even without total destruction of the vestibular neurosensory epithelium, provides relief of hydrops. This is believed to account for documented cases of persistent caloric response following intratympanic gentamicin

GENTAMICIN THERAPY IN NONSERVICEABLE EARS 115 therapy with relief of the symptoms of hydrops. 3,4,5,7 Third, slow destruction of the vestibular end organ with intratympanic gentamicin, in contrast to the immediate destruction with labyrinthectomy or nerve section, may allow the central vestibular system to compensate more effectively. No publication has reported on long-term failure rates with the use of intratympanic gentamicin. In this study, the patient sample size is small and follow-up is in the intermediate range; however, like labyrinthectomy, failures are expected. Even if symptoms of vertigo return, there is little potential harm in repeating intratympanic gentamicin therapy. Further, all therapeutic options are still available. If the patient tires of repeated injections, or if injections fail to relieve symptoms of vertigo in the future, there is no contraindication to proceeding with labyrinthectomy at that time. CONCLUSION In our series of patients with nonserviceable hearing, intratympanic gentamicin was effective in relieving vertigo. Intratympanic gentamicin therapy offers a minimally invasive, cost-effective, low-morbidity means of managing vertigo in patients with nonserviceable hearing. REFERENCES 1. Schuknecht HF: Ablation therapy in the management of Meniere s disease. Acta Otolaryngol 132:1-42, 1957 (suppl) 2. Beck C, Schmidt CL: 10 years of experience with intratympanically applied streptomycin (gentamicin) in the therapy of morbus Meniere. Arch Otorhinolaryngol 221:149-152, 1978 3. Driscoll CLW, Kasperbauer JL, Facer GW, et al: Low-dose intratympanic gentamicin and the treatment of meniere s disease: Preliminary results. Laryngoscope 107: 83-89, 1997 4. Hirsch BE, Kamerer DB: Intratympanic gentamicin therapy for Meniere s disease. Am J Otol 18:44-51, 1997 5. Murofushi T, Halmagyi GM, Yavor RA: Intratympanic gentamicin in Meniere s disease: Results of therapy. Am J Otol 18:52-57, 1997 6. Rauch SD, Oas JG: Intratympanic gentamicin for treatment of intractable Meniere s disease: A preliminary report. Laryngoscope 107:49-55, 1997 7. Nedzelski JM, Chiong CM, Fradet G, et al: Intratympanic gentamicin instillation as treatment of unilateral Meniere s disease: Update of an ongoing study. Am J Otol 14:278-282, 1993 8. Brantberg K, Bergenius J, Tribukait A: Gentamicin treatment in peripheral vestibular disorders other than Meniere s disease. ORL J Otorhinolaryngol Relat Spec 58:277-279, 1996 9. Schuknecht HF: Delayed endolymphatic hydrops. Ann Otol Rhinol Laryngol 87:743-748, 1978 10. Committee on Hearing and Equilibrium: Committee on hearing and equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere s disease. Otolaryngol Head Neck Surg 113:181-185, 1995 11. Langman AW, Linderman RC: Surgery for vertigo in the nonserviceable hearing ear: Transmastoid labyrinthectomy or translabyrinthine vestibular nerve section. Laryngoscope 103:1321-1325, 1993 12. Graham MD, Goldsmith MM: Labyrinthectomy. Indications and surgical technique. Otolaryngol Clin North Am 27:325-335, 1994 13. Yazdi AK, Rutka J: Results of labyrinthectomy in the treatment of Meniere s disease and delayed endolymphatic hydrops. J Otolaryngol 25:26-31, 1996 14. Gacek RR, Gacek MR: Comparison of labyrinthectomy and vestibular neurectomy in the control of vertigo. Laryngoscope 106:225-230, 1996 15. Parnes LS, Riddell D: Irritative spontaneous nystagmus following intratympanic gentamicin for Meniere s disease. Laryngoscope 103:745-749, 1993 16. Cass SP, Kartush JM, Graham MD: Patterns of vestibular function following vestibular nerve section. Laryngoscope 102:388-394, 1992 17. Li CW, Cousins V, Hooper R: Vestibulo-ocular compensation following unilateral vestibular deafferentation. Ann Otol Rhinol Laryngol 101:525-529, 1992 18. Pender DJ: Gentamicin tympanoclysis: Effects on the vestibular secretory cells. Am J Otolaryngol 6:358-367, 1985 19. Monsell EM, Cass SP, Rybak LP: Therapeutic use of aminoglycosides in Meniere s disease. Otolaryngol Clin North Am 26:737-746, 1993