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Continuous intratympanic infusion of gentamicin via a microcatheter in Menière's disease
Continuous intratympanic infusion of gentamicin via a microcatheter in Menière’s disease JAKOB SCHOENDORF, PETER NEUGEBAUER, and OLAF MICHEL, Cologne, Germany
Between 1995 and 1998, 11 patients with disabling Menière’s disease were treated at our institution with a continuous gentamicin infusion into the middle ear via a microcatheter. The patients had frequent attacks of vertigo and vomiting (functional levels 3-5). Hearing threshold on the affected side was significantly worse than on the healthy side (stage 4+5). Gentamicin was applied by a high-precision insulin pump with a flow rate of 40 mg per day directly in front of the round window. Application was stopped as soon as signs of vestibular affection appeared. A good overall control of vertiginous spells was achieved in 8 patients. Eight patients experienced complete hearing loss on the affected side, 1 experienced a slight worsening, and 1 had no hearing change. There was no correlation between the cumulative gentamicin dosage and the hearing loss. Our findings show that in terms of hearing loss and hospitalization time the continuous gentamicin application is inferior to other applications presented in the literature. (Otolaryngol Head Neck Surg 2001;124:203-7.)
In 80% of patients with Menière’s disease, nonsurgical treatment is considered to be effective in controlling the symptoms. In cases where conservative medical and dietary treatment has failed, the use of aminoglycosides is proposed as an equivalent alternative to surgical procedures. Aminoglycosides have been used since the 1950s in the treatment of intractable Menière’s disease. During the 1970s, gentamicin became more popular than streptomicin.1 The drug is applied either systemically (used to treat bilateral disease)2 or topically by instillation into the middle ear of the affected side. The intratympanic application has been used by many otolaryngologists. Because of the risk of hearing loss, attempts are made to reduce the total amount of genFrom the Department of Otorhinolaryngology, University of Cologne. Supported by the Jean-Uhrmacher-Foundation. Reprint requests: Dr Jakob Schoendorf, Department of Otorhinolaryngology (HNO), Joseph-Stelzmann-Strasse 9, D-50924 Cologne; e-mail: [email protected] Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/77/112310 doi:10.1067/mhn.2001.112310
tamicin. Until now the optimal dosage has not been found. The usual doses are within a range between 20 mg3 and 400 mg4 (see Table 1). The regimen varies from author to author. Some propose a rather rigid regimen with a certain dose given over a certain period of time,5 others instill the gentamicin until signs of vestibular affliction are seen6 or give initial doses with repeated administrations only when attacks recur.3,7 There is also no common means of administration. The techniques include simple injections with long needles,3,7-10 through ventilation tubes,1,11 through microcatheters that are placed into the tympanic membrane,12,13 or behind the annulus fibrosus emerging in front of the round window niche.6 The injections are either given by the doctor, by the patient’s relatives,4 or by a microinfusion pump.6 A microcatheter was placed in front of the round window niche and a high-precision insulin pump was used. The aim was to find the lowest individual dose and therefore to shorten hospitalization time. A local inflammatory reaction to the medicament and time-consuming injections are avoided in order to make the patient as comfortable as possible during treatment. The patients were not asked to do anything more than to tell whether they had further symptoms. METHODS AND MATERIAL Subjects From 1995 to 1998, 11 patients received the continuous intratympanic infusion of gentamicin (Table 2). Ten had a unilateral and 1 a bilateral Menière’s disease, all with an average history of more than 4 years. Medical treatment had been unsuccessful. The disease according to the AAO Guidelines14 was stage 3 in 8 patients and stage 4 in 3 patients. All patients were hospitalized and investigated with pure-tone audiometry before treatment. Average hearing threshold of the affected ear was 45 to 86 dB (average, 67.3 dB). Only 6 patients presented a normal response to caloric stimulation before gentamicin therapy. The patients’ ages ranged from 32 to 69 years at time of surgery. The frequency of vertigo attacks before treatment ranged from 7 times daily to once a week. Attacks were usually accompanied by vomiting. The functional level according to the AAO Guidelines1 is shown in Table 3. Material To provide a constant flow of gentamicin, a high-precision insulin pump was used (H-tron C 100, Disetronic 203
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Table 1. Dosage and deafened ears reported in other publications Author
Ödkvist et al9 Lange21 Hoffmann et al5 Nedzelski et al22 Küppers et al6 Lange1 Corsten et al11 Driscoll et al3 Murofushi et al8 Rauch et al16 Sala10 Harner et al18 Kaasinen et al7 McFeely et al4 Mondain et al15 Pfleiderer13 Lange19
Year
No.
Dose (mg)
Deaf ears
1984 1985 1993 1993 1994 1995 1997 1997 1997 1997 1997 1998 1998 1998 1998 1998 1999
16 nn* 20 30 28 61 21 23 18 21 21 43 93 25 12 24 15
189 100-500 168 Max 320 95 (31-205) 300 216 47 (10-80) 30-150 24-168 37.5-75 nn* 36.3 320-400 107.65 208.2 12-48
7 (44%) ~30% 1 (5%) 2 (7%) None 29 (48%)† nn* nn* 5 (28%) 3 (14%) nn* None 10 (11%) 5 (20%) 1 (8%) 1 (4%) None
*nn, No numbers. †, Includes pretherapeutic deafness.
Medical Systems, Sulzbach, Germany). A 28 g microcatheter with an inner diameter of 0.3 mm (usually used for continuous spinal anesthesia) was connected to the pump with a bacterial filter interposed. Surgical Procedure The patient was given a local anesthesia and an endaural incision according to Heermann was made to gain more access. A circumferential incision was made to form the tympanomeatal flap, which was elevated in order to visualize the middle ear. The catheter was then introduced in a Seldinger technique from behind the ear. The opening of the catheter was carefully positioned in front of the round window niche and fixed by a vicryl suture within the endaural incision. After wound closure, antibiotic soaked packing was placed in the ear canal. Therapy Regimen Gentamicin sulfate (Refobacin, Merck, Darmstadt, Germany) was given in a dose of 40 mg per day. The patients were advised to stay at rest with the head slightly turned. They were observed for nystagmus by Frenzel glasses every 3 hours. When the patient experienced vertigo and/or a spontaneous nystagmus, the pump was stopped immediately and the middle ear cavity was rinsed with Ringer solution. The catheter was then removed without complications. Follow-up Ten patients were followed up postoperatively during a period of 3 months to 1 year or are still regularly seen. One patient was followed up at a different hospital and was therefore not included in the evaluation. Postoperative examina-
Table 2. Patients treated and staged according to the AAO-HNS guidelines using 4-tone average14 Average age at time of treatment (yrs) Gender Female Male Average duration of disease (months) Stages 1 (≤25 dB) 2 (26-40 dB) 3 (41-70 dB) 4 (>70 dB)
51.6
7 4 49
0 0 8 3
tions consisted of pure tone audiometry and caloric testing of the vestibular organ. A rotating chair examination assessed central compensation of peripheral vestibular dysfunction. RESULTS
The spontaneous nystagmus appeared in 2 patients on the second day of treatment, 2 showed the first nystagmus only after 13 days. The average onset of spontaneous nystagmus was 6.7 days. That meant an average total dose of 309 mg gentamicin (range, 60 to 720 mg). In most cases, the patients showed moderate to severe signs of disequilibrium and discomfort after the infusion was ended and were therefore observed for several more days. Mean hospitalization time was 11.9 days. The exact data are shown in Table 4. Effect on Vertigo
Before treatment, a normal reaction to caloric stimulation was present in 6 patients. Three patients had a hypoactive reaction, and 2 had no reaction to caloric testing on the affected side. After the treatment, 6 patients had no response to caloric testing of the treated ear, 4 patients had hypoactivity. One patient had a severe attack of vertigo shortly after discharge and was taken to a different hospital by paramedics, where she received further gentamicin through a ventilating tube; further examinations were also done in that hospital. During follow-up, 4 of the 10 resting patients complained about attacks of rotatory vertigo, but these appeared to be less frequent. One of these patients had bilateral disease with a decrease of the frequency of attacks by half. Two years after treatment, the attacks of this patient are again getting worse. They originate on the untreated side and appear 4 times per month, two thirds of the rate before treatment. The other 3 patients achieve a substantial vertigo control with a frequency of 1 to 3 episodes per month. One patient has had only 1
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Table 3. Functional level of the patients (according to the AAO-HNS Guidelines) pretreatment and posttreatment Functional level
Pretreatment
1. My dizziness has no effect on my activities at all. 2. When I am dizzy I have to stop what I am doing for a while, but soon it passes and I can resume activities. I continue to work. 3. When I am dizzy I have to stop what I am doing for a while, but it does pass and I can resume activities. I continue to work, drive, and engage in most activities I choose, but I have had to change some plans and make some allowance for my dizziness. 4. I am able to work, drive, travel, take care of a family, or engage in most essential activities, but I must exert a great deal of effort to do so. I must constantly make adjustments in my activities and budget my energies. I am barely making it. 5. I am unable to work, drive, or take care of a family. I am unable to do most of the active things that I used to. Even essential activities must be limited. I am disabled. 6. I have been disabled for 1 year or longer and/or I receive compensation (money) because of my dizziness or balance problem.
Posttreatment
0 0
4 2
1
0
6
2
4
2
0
(1)*
*This patient was followed up at a different hospital.
Table 4. Data of patients included in the evaluation Patient no.
Cumulative dose (mg)
1 2 3 4 5 6 7 8 9 10 Average
440 320 720 470 110 240 60 320 70 340 309
Days until onset of SN
13 8 10 7 3 4 2 4 2 13 6.7
Hospitalization time (days)
23 14 12 10 8 10 6 15 5 16 11.9
Hearing threshold pretreatment (dB)
67 59 46.6 86 57 58 78 45 67 71 67.3
Hearing threshold posttreatment (dB)
>120 94 >120 >120 >120 56 >120 >120 >120 >120 >110
Caloric Caloric paresis paresis paresis pretreatment (%) posttreatment (%)
0.5 6.6 100 59.9 100 15.6 51.3 84.8 32.33 28.8 48
87.5 100 100 100 100 100 89.6 85.8 100 50.8 91.4
SN, Spontaneous nystagmus.
further episode during the 2 years since treatment. Altogether 4 patients were able to resume their normal activities (see Table 3). The classification of the results is shown in Table 5. The attacks of rotatory vertigo are not the only complaints of the patients. Other symptoms are constant unsteadiness and dizziness, insecure gait in dark rooms, very short episodes (a few seconds) of losing control over balance or gait (Tumarkin attacks), and instability of the field of vision when turning the head (see Table 6). The 2 patients who complained about constant dizziness showed no spontaneous nystagmus during all control visits and rotating chair–testing presented symmetric reactions as a sign of central compensation. Effect on Hearing
The average hearing threshold before treatment was 67.3 dB on the affected ear. After the treatment, 8 patients
became deaf on the treated side. One had unchanged hearing, and one was worse (Table 4). Although some patients took the deafness well, others felt bothered. DISCUSSION
The intratympanic use of gentamicin is a well-recognized alternative to such surgical procedures as labyrinthectomy, selective vestibular nerve section, or endolymphatic sac operation. Even when a catheter is implanted during a tympanoscopy, it is still less invasive than other surgical methods. A review of the literature15 shows that full or at least substantial control of vertigo is achieved in about 88% of the patients. This number is comparable to the results of neurectomy (92%) and better than those of endolymphatic sac operation (71.7%).15 In approximately two thirds of the patients, hearing is unchanged or better. Only small numbers of deafened ears are reported in the literature.4,5,12,16
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Table 5. Treatment evaluation according to the AAO-HNS guidelines: 100 × X/Y (X, definitive vertiginous spells per month during months 18 to 24 after treatment; Y, the definitive spells per month during 6 months before therapy) Class
A (0) B (1-40) C (41-80) D (81-120) E ( > 120) F (secondary treatment initiated due to disability from vertigo)
n
6 2 1 1 0 1
In our evaluation, attacks of rotatory vertigo ceased completely in 6 patients; for 2 patients substantial control was achieved. The classification according to the AAO-HNS guidelines is presented in Table 5. The outcome of vertigo did not seem to correlate with the loss of caloric response after treatment. A patient with no response to caloric stimulation continued to have occasional attacks of rotatory vertigo. On the other hand, no further vertiginous spells were seen in a patient with only a 50% reduction of caloric activity. It has been pointed out in other publications5,11 that a total ablation of vestibular function is not necessary to control vertigo in Menière’s disease. Also a complete absence of caloric response does not guarantee successful treatment.1,4 Only 4 patients have been completely satisfied with the treatment. Constant dizziness was present in 5 patients; for 2 it was the most bothersome symptom at this time. This symptom was described in distinct contrast to the attacks of rotatory vertigo by the patients. The dizziness occurred either periodically (depending on the weather) or was constantly present, though it was not noticed before treatment. Of these patients, 3 had no reaction to caloric stimulation after therapy, 2 still had very little reaction. For 1 patient, the period of central compensation was delayed for more than 2 months. Insufficiency of the basilar artery is the suspected cause for this patient’s symptoms but this is still not proven. The other 3 patients had symmetric reactions to rotating chair testing. An explanation for this dizziness might be insufficient habituation exercise after treatment or inadequate plasticity of the brain. A similar complaint has not yet been mentioned in the reviewed literature. Insecure gait especially in the dark was described by all patients in the first 2 weeks after treatment. Seven patients still experience instability in dark rooms, 5 of them even in daylight. Kaasinen et al7 regard postural control as the most important factor determining the
Table 6. Other symptoms disturbing patients after treatment Symptoms
Constant unsteadiness and dizziness Insecure gait in the dark Insecure gait Very short episodes of balance loss Instability of the field of vision when turning the head Feel bothered by the deafness on the treated ear
n
4 7 5 2 5 4
outcome of the treatment. As in other publications,15 stress is put on the habituation exercises. Two of our patients were not motivated to do exercises because they felt too dizzy to do them. The aforementioned theoretical explanations may also apply. Two subjects described very short episodes of losing balance and discomforting feelings of insecurity. These attacks might correspond to the Tumarkin attacks described by other publications.7 They are not dependent on the vestibular function after therapy. In one case, there was no caloric response left. These attacks are believed to originate from the otolith organs. This would give reason to believe that the absence of caloric response does not prove complete loss of vestibular function. Delayed adjustment of the field of vision when turning the head was reported by 5 subjects after therapy. Allison et al17 showed that after gentamicin treatment the vestibulo-ocular reflex time is prolonged for rapid passive head turns in the direction of the vestibular deficit. This might be true also for active head turns when vestibulo-ocular and cervico-ocular reflexes are responsible for keeping a steady image on the retina. There is also no correlation between the caloric response after treatment and the appearance of this phenomenon. The effect on hearing was disappointing. Before treatment all patients had an average hearing threshold of more than 45 dB. One patient was almost deaf on the affected side as a result of previous ear surgery because of chronic middle ear disease. After treatment, hearing was preserved in only 1 patient. Another had a decrease of hearing threshold of more than 30 dB, and 8 became deaf in the bad ear. There was no obvious correlation between the loss of hearing and the total dose of gentamicin. Although the cumulative dose for 1 patient was as high as 720 mg, deafness was also seen with only 60 mg. The unchanged hearing was preserved after administration of 240 mg. Hoffmann et al5 stated that patients who already had significantly worsened hearing are more likely to develop further decrease of the hearing threshold. Kaasinen et al7 reports 2 deaf ears after injection of only 30 mg of gentamicin, Murofushi et al9 after
Otolaryngology– Head and Neck Surgery Volume 124 Number 2
60 mg. This indicates that there is no safe amount of gentamicin, although it is evident that low doses should be used. The application of 1 single dose is now recommended in some publications.18,19 It is also not known how much gentamicin gets lost through the Eustachian tube and never passes the round window membrane. Some otolaryngologists give advice that the head should be turned with the affected side down during instillation. That way the loss of fluid through the eustachian tube should be avoided. The use of a continuous middle ear perfusion was thought suitable to ascertain to the lowest individual dose. Titration was halted when signs of vestibular affliction became evident. Küppers et al6 observed good vertigo control and no deaf ears in that way. Magnusson et al12 found that there was a delay between the administration of an ototoxic agent and its effect on the cochlea and the vestibular function. This suggests that during a continuous perfusion the adequate dose might be quickly exceeded unnoticed. Therefore, it is also likely that hospitalization time is extended unnecessarily. This stands in contrast to treatment on an outpatient base.3,4 We conclude that the continuous gentamicin perfusion is of no advantage over other applications in terms of effect on hearing and hospitalization time. With 60% of the patients having achieved a functional level of 2 or better, our results are comparable with those presented by Kerr and Toner.20 Sixty percent of their patients already selected for surgery improved after the authors had merely talked to them about surgery and had given them time to think about the procedure. For these 60%, an invasive procedure could be avoided. REFERENCES 1. Lange G. 27 Jahre Erfahrung mit der transtympanalen Aminoglycosid-Behandlung des Morbus Menière. Laryngol Rhinol Otol 1995;74:720-3. 2. Balyan FR, Teibah A, De Donato G, et al. Titration streptomycin therapy in Menière’s disease: long-term results. Otolaryngol Head Neck Surg 1998;118:261-6. 3. Driscoll CLW, Kasperbauer JL, Facer GW, et al. Low-dose intratympanic gentamicin and the treatment of Menière’s disease: preliminary results. Laryngoscope 1997;107:83-9.
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4. McFeely WJ, Singleton GT, Rodriguez FJ, et al. Intratympanic gentamicin treatment for Menière’s disease. Otolaryngol Head Neck Surg 1998;118:587-96. 5. Hoffmann F, Beck C, Beck C, et al. Subablative Gentamicintherapie bei M. Menière. HNO 1993;41:296-300. 6. Küppers P, Ahrens H, Blessing R. Die kontinuierliche intratympanale Gentamicininfusion beim Morbus Menière. HNO 1994;42:429-33. 7. Kaasinen S, Pyykkö I, Ishizaki H, et al. Intratympanic gentamicin in Menière’s disease. Acta Otolaryngol 1998;118:294-8. 8. Murofushi T, Halmagyi GM, Yavor RA. Intratympanic gentamicin in Menière’s disease: results of therapy. Am J Otol 1997;18:52-7. 9. Ödkvist LM, Bergholtz LM, Lundgren A. Topical Gentamycin treatment for disabling Menière’s disease. Acta Otolaryngol 1984;412(Suppl):74-6. 10. Sala T. Transtympanic gentamicin in the treatment of Menière’s disease. Auri Nasus Larynx 1997;24:239-46. 11. Corsten M, Marsan J, Schramm D, et al. Treatment of intractable Menière’s disease with intratympanic gentamicin: review of the University of Ottawa experience. J Otolaryngol 1997;26:361-4. 12. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Menière’s disease. Acta Otolaryngol 1991;111:671-6. 13. Pfleiderer AG. The current role of local intratympanic gentamicin therapy in the management of unilateral Menière’s disease. Clin Otolaryngol 1998;23:34-41. 14. AAO-HNS Committee on Hearing and Equilibrium. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. Otolaryngol Head Neck Surg 1995;113:181-5. 15. Mondain M, Mouchet F, Marlier F, et al. Labyrinthectomie chimique: résultats et intérêt. Ann Otolaryngol Chir Cervicofac 1998;115:234-42. 16. Rauch SD, Oas JG. Intratympanic gentamicin for treatment of intractable Menière’s disease: a preliminary report. Laryngoscope 1997;107:49-55. 17. Allison RS, Eizenmann M, Tomlinson RD, et al. Vestibulo-ocular reflex deficits to rapid head turns following intratympanic gentamicin instillation. J Vestib Res 1997;7:369-80. 18. Harner SG, Kasperbauer MD, Facer GW, et al. Transtympanic gentamicin for Menière’ syndrome. Laryngoscope 1998;108: 1446-9. 19. Lange G. Transtympanic injections facilitate gentamicin treatment for Menière’s disease. 4th international symposium on Menière’s disease, Paris 1999. 20. Kerr AG, Toner JG. A new approach to surgery for Menière’s disease: talking about surgery. Clin Otolaryngol 1998;23:263-4. 21. Lange G Technische Schwierigkeiten bei der intratympanalen gentamycintherapie des Morbus Menière. Laryngol Rhinol Otol 1985;64:174. 22. Nedzelski JM, Chiong CM, Fradet G, et al. Intratympanic Gentamicin instillation as treatment of unilateral Menière’s disease: update of an ongoing study. Am J Otol 1993;14:278-82.
Between 1995 and 1998, 11 patients with disabling Menière’s disease were treated at our institution with a continuous gentamicin infusion into the middle ear via a microcatheter. The patients had frequent attacks of vertigo and vomiting (functional levels 3-5). Hearing threshold on the affected side was significantly worse than on the healthy side (stage 4+5). Gentamicin was applied by a high-precision insulin pump with a flow rate of 40 mg per day directly in front of the round window. Application was stopped as soon as signs of vestibular affection appeared. A good overall control of vertiginous spells was achieved in 8 patients. Eight patients experienced complete hearing loss on the affected side, 1 experienced a slight worsening, and 1 had no hearing change. There was no correlation between the cumulative gentamicin dosage and the hearing loss. Our findings show that in terms of hearing loss and hospitalization time the continuous gentamicin application is inferior to other applications presented in the literature. (Otolaryngol Head Neck Surg 2001;124:203-7.)
In 80% of patients with Menière’s disease, nonsurgical treatment is considered to be effective in controlling the symptoms. In cases where conservative medical and dietary treatment has failed, the use of aminoglycosides is proposed as an equivalent alternative to surgical procedures. Aminoglycosides have been used since the 1950s in the treatment of intractable Menière’s disease. During the 1970s, gentamicin became more popular than streptomicin.1 The drug is applied either systemically (used to treat bilateral disease)2 or topically by instillation into the middle ear of the affected side. The intratympanic application has been used by many otolaryngologists. Because of the risk of hearing loss, attempts are made to reduce the total amount of genFrom the Department of Otorhinolaryngology, University of Cologne. Supported by the Jean-Uhrmacher-Foundation. Reprint requests: Dr Jakob Schoendorf, Department of Otorhinolaryngology (HNO), Joseph-Stelzmann-Strasse 9, D-50924 Cologne; e-mail: [email protected] Copyright © 2001 by the American Academy of Otolaryngology– Head and Neck Surgery Foundation, Inc. 0194-5998/2001/$35.00 + 0 23/77/112310 doi:10.1067/mhn.2001.112310
tamicin. Until now the optimal dosage has not been found. The usual doses are within a range between 20 mg3 and 400 mg4 (see Table 1). The regimen varies from author to author. Some propose a rather rigid regimen with a certain dose given over a certain period of time,5 others instill the gentamicin until signs of vestibular affliction are seen6 or give initial doses with repeated administrations only when attacks recur.3,7 There is also no common means of administration. The techniques include simple injections with long needles,3,7-10 through ventilation tubes,1,11 through microcatheters that are placed into the tympanic membrane,12,13 or behind the annulus fibrosus emerging in front of the round window niche.6 The injections are either given by the doctor, by the patient’s relatives,4 or by a microinfusion pump.6 A microcatheter was placed in front of the round window niche and a high-precision insulin pump was used. The aim was to find the lowest individual dose and therefore to shorten hospitalization time. A local inflammatory reaction to the medicament and time-consuming injections are avoided in order to make the patient as comfortable as possible during treatment. The patients were not asked to do anything more than to tell whether they had further symptoms. METHODS AND MATERIAL Subjects From 1995 to 1998, 11 patients received the continuous intratympanic infusion of gentamicin (Table 2). Ten had a unilateral and 1 a bilateral Menière’s disease, all with an average history of more than 4 years. Medical treatment had been unsuccessful. The disease according to the AAO Guidelines14 was stage 3 in 8 patients and stage 4 in 3 patients. All patients were hospitalized and investigated with pure-tone audiometry before treatment. Average hearing threshold of the affected ear was 45 to 86 dB (average, 67.3 dB). Only 6 patients presented a normal response to caloric stimulation before gentamicin therapy. The patients’ ages ranged from 32 to 69 years at time of surgery. The frequency of vertigo attacks before treatment ranged from 7 times daily to once a week. Attacks were usually accompanied by vomiting. The functional level according to the AAO Guidelines1 is shown in Table 3. Material To provide a constant flow of gentamicin, a high-precision insulin pump was used (H-tron C 100, Disetronic 203
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Table 1. Dosage and deafened ears reported in other publications Author
Ödkvist et al9 Lange21 Hoffmann et al5 Nedzelski et al22 Küppers et al6 Lange1 Corsten et al11 Driscoll et al3 Murofushi et al8 Rauch et al16 Sala10 Harner et al18 Kaasinen et al7 McFeely et al4 Mondain et al15 Pfleiderer13 Lange19
Year
No.
Dose (mg)
Deaf ears
1984 1985 1993 1993 1994 1995 1997 1997 1997 1997 1997 1998 1998 1998 1998 1998 1999
16 nn* 20 30 28 61 21 23 18 21 21 43 93 25 12 24 15
189 100-500 168 Max 320 95 (31-205) 300 216 47 (10-80) 30-150 24-168 37.5-75 nn* 36.3 320-400 107.65 208.2 12-48
7 (44%) ~30% 1 (5%) 2 (7%) None 29 (48%)† nn* nn* 5 (28%) 3 (14%) nn* None 10 (11%) 5 (20%) 1 (8%) 1 (4%) None
*nn, No numbers. †, Includes pretherapeutic deafness.
Medical Systems, Sulzbach, Germany). A 28 g microcatheter with an inner diameter of 0.3 mm (usually used for continuous spinal anesthesia) was connected to the pump with a bacterial filter interposed. Surgical Procedure The patient was given a local anesthesia and an endaural incision according to Heermann was made to gain more access. A circumferential incision was made to form the tympanomeatal flap, which was elevated in order to visualize the middle ear. The catheter was then introduced in a Seldinger technique from behind the ear. The opening of the catheter was carefully positioned in front of the round window niche and fixed by a vicryl suture within the endaural incision. After wound closure, antibiotic soaked packing was placed in the ear canal. Therapy Regimen Gentamicin sulfate (Refobacin, Merck, Darmstadt, Germany) was given in a dose of 40 mg per day. The patients were advised to stay at rest with the head slightly turned. They were observed for nystagmus by Frenzel glasses every 3 hours. When the patient experienced vertigo and/or a spontaneous nystagmus, the pump was stopped immediately and the middle ear cavity was rinsed with Ringer solution. The catheter was then removed without complications. Follow-up Ten patients were followed up postoperatively during a period of 3 months to 1 year or are still regularly seen. One patient was followed up at a different hospital and was therefore not included in the evaluation. Postoperative examina-
Table 2. Patients treated and staged according to the AAO-HNS guidelines using 4-tone average14 Average age at time of treatment (yrs) Gender Female Male Average duration of disease (months) Stages 1 (≤25 dB) 2 (26-40 dB) 3 (41-70 dB) 4 (>70 dB)
51.6
7 4 49
0 0 8 3
tions consisted of pure tone audiometry and caloric testing of the vestibular organ. A rotating chair examination assessed central compensation of peripheral vestibular dysfunction. RESULTS
The spontaneous nystagmus appeared in 2 patients on the second day of treatment, 2 showed the first nystagmus only after 13 days. The average onset of spontaneous nystagmus was 6.7 days. That meant an average total dose of 309 mg gentamicin (range, 60 to 720 mg). In most cases, the patients showed moderate to severe signs of disequilibrium and discomfort after the infusion was ended and were therefore observed for several more days. Mean hospitalization time was 11.9 days. The exact data are shown in Table 4. Effect on Vertigo
Before treatment, a normal reaction to caloric stimulation was present in 6 patients. Three patients had a hypoactive reaction, and 2 had no reaction to caloric testing on the affected side. After the treatment, 6 patients had no response to caloric testing of the treated ear, 4 patients had hypoactivity. One patient had a severe attack of vertigo shortly after discharge and was taken to a different hospital by paramedics, where she received further gentamicin through a ventilating tube; further examinations were also done in that hospital. During follow-up, 4 of the 10 resting patients complained about attacks of rotatory vertigo, but these appeared to be less frequent. One of these patients had bilateral disease with a decrease of the frequency of attacks by half. Two years after treatment, the attacks of this patient are again getting worse. They originate on the untreated side and appear 4 times per month, two thirds of the rate before treatment. The other 3 patients achieve a substantial vertigo control with a frequency of 1 to 3 episodes per month. One patient has had only 1
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Table 3. Functional level of the patients (according to the AAO-HNS Guidelines) pretreatment and posttreatment Functional level
Pretreatment
1. My dizziness has no effect on my activities at all. 2. When I am dizzy I have to stop what I am doing for a while, but soon it passes and I can resume activities. I continue to work. 3. When I am dizzy I have to stop what I am doing for a while, but it does pass and I can resume activities. I continue to work, drive, and engage in most activities I choose, but I have had to change some plans and make some allowance for my dizziness. 4. I am able to work, drive, travel, take care of a family, or engage in most essential activities, but I must exert a great deal of effort to do so. I must constantly make adjustments in my activities and budget my energies. I am barely making it. 5. I am unable to work, drive, or take care of a family. I am unable to do most of the active things that I used to. Even essential activities must be limited. I am disabled. 6. I have been disabled for 1 year or longer and/or I receive compensation (money) because of my dizziness or balance problem.
Posttreatment
0 0
4 2
1
0
6
2
4
2
0
(1)*
*This patient was followed up at a different hospital.
Table 4. Data of patients included in the evaluation Patient no.
Cumulative dose (mg)
1 2 3 4 5 6 7 8 9 10 Average
440 320 720 470 110 240 60 320 70 340 309
Days until onset of SN
13 8 10 7 3 4 2 4 2 13 6.7
Hospitalization time (days)
23 14 12 10 8 10 6 15 5 16 11.9
Hearing threshold pretreatment (dB)
67 59 46.6 86 57 58 78 45 67 71 67.3
Hearing threshold posttreatment (dB)
>120 94 >120 >120 >120 56 >120 >120 >120 >120 >110
Caloric Caloric paresis paresis paresis pretreatment (%) posttreatment (%)
0.5 6.6 100 59.9 100 15.6 51.3 84.8 32.33 28.8 48
87.5 100 100 100 100 100 89.6 85.8 100 50.8 91.4
SN, Spontaneous nystagmus.
further episode during the 2 years since treatment. Altogether 4 patients were able to resume their normal activities (see Table 3). The classification of the results is shown in Table 5. The attacks of rotatory vertigo are not the only complaints of the patients. Other symptoms are constant unsteadiness and dizziness, insecure gait in dark rooms, very short episodes (a few seconds) of losing control over balance or gait (Tumarkin attacks), and instability of the field of vision when turning the head (see Table 6). The 2 patients who complained about constant dizziness showed no spontaneous nystagmus during all control visits and rotating chair–testing presented symmetric reactions as a sign of central compensation. Effect on Hearing
The average hearing threshold before treatment was 67.3 dB on the affected ear. After the treatment, 8 patients
became deaf on the treated side. One had unchanged hearing, and one was worse (Table 4). Although some patients took the deafness well, others felt bothered. DISCUSSION
The intratympanic use of gentamicin is a well-recognized alternative to such surgical procedures as labyrinthectomy, selective vestibular nerve section, or endolymphatic sac operation. Even when a catheter is implanted during a tympanoscopy, it is still less invasive than other surgical methods. A review of the literature15 shows that full or at least substantial control of vertigo is achieved in about 88% of the patients. This number is comparable to the results of neurectomy (92%) and better than those of endolymphatic sac operation (71.7%).15 In approximately two thirds of the patients, hearing is unchanged or better. Only small numbers of deafened ears are reported in the literature.4,5,12,16
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Table 5. Treatment evaluation according to the AAO-HNS guidelines: 100 × X/Y (X, definitive vertiginous spells per month during months 18 to 24 after treatment; Y, the definitive spells per month during 6 months before therapy) Class
A (0) B (1-40) C (41-80) D (81-120) E ( > 120) F (secondary treatment initiated due to disability from vertigo)
n
6 2 1 1 0 1
In our evaluation, attacks of rotatory vertigo ceased completely in 6 patients; for 2 patients substantial control was achieved. The classification according to the AAO-HNS guidelines is presented in Table 5. The outcome of vertigo did not seem to correlate with the loss of caloric response after treatment. A patient with no response to caloric stimulation continued to have occasional attacks of rotatory vertigo. On the other hand, no further vertiginous spells were seen in a patient with only a 50% reduction of caloric activity. It has been pointed out in other publications5,11 that a total ablation of vestibular function is not necessary to control vertigo in Menière’s disease. Also a complete absence of caloric response does not guarantee successful treatment.1,4 Only 4 patients have been completely satisfied with the treatment. Constant dizziness was present in 5 patients; for 2 it was the most bothersome symptom at this time. This symptom was described in distinct contrast to the attacks of rotatory vertigo by the patients. The dizziness occurred either periodically (depending on the weather) or was constantly present, though it was not noticed before treatment. Of these patients, 3 had no reaction to caloric stimulation after therapy, 2 still had very little reaction. For 1 patient, the period of central compensation was delayed for more than 2 months. Insufficiency of the basilar artery is the suspected cause for this patient’s symptoms but this is still not proven. The other 3 patients had symmetric reactions to rotating chair testing. An explanation for this dizziness might be insufficient habituation exercise after treatment or inadequate plasticity of the brain. A similar complaint has not yet been mentioned in the reviewed literature. Insecure gait especially in the dark was described by all patients in the first 2 weeks after treatment. Seven patients still experience instability in dark rooms, 5 of them even in daylight. Kaasinen et al7 regard postural control as the most important factor determining the
Table 6. Other symptoms disturbing patients after treatment Symptoms
Constant unsteadiness and dizziness Insecure gait in the dark Insecure gait Very short episodes of balance loss Instability of the field of vision when turning the head Feel bothered by the deafness on the treated ear
n
4 7 5 2 5 4
outcome of the treatment. As in other publications,15 stress is put on the habituation exercises. Two of our patients were not motivated to do exercises because they felt too dizzy to do them. The aforementioned theoretical explanations may also apply. Two subjects described very short episodes of losing balance and discomforting feelings of insecurity. These attacks might correspond to the Tumarkin attacks described by other publications.7 They are not dependent on the vestibular function after therapy. In one case, there was no caloric response left. These attacks are believed to originate from the otolith organs. This would give reason to believe that the absence of caloric response does not prove complete loss of vestibular function. Delayed adjustment of the field of vision when turning the head was reported by 5 subjects after therapy. Allison et al17 showed that after gentamicin treatment the vestibulo-ocular reflex time is prolonged for rapid passive head turns in the direction of the vestibular deficit. This might be true also for active head turns when vestibulo-ocular and cervico-ocular reflexes are responsible for keeping a steady image on the retina. There is also no correlation between the caloric response after treatment and the appearance of this phenomenon. The effect on hearing was disappointing. Before treatment all patients had an average hearing threshold of more than 45 dB. One patient was almost deaf on the affected side as a result of previous ear surgery because of chronic middle ear disease. After treatment, hearing was preserved in only 1 patient. Another had a decrease of hearing threshold of more than 30 dB, and 8 became deaf in the bad ear. There was no obvious correlation between the loss of hearing and the total dose of gentamicin. Although the cumulative dose for 1 patient was as high as 720 mg, deafness was also seen with only 60 mg. The unchanged hearing was preserved after administration of 240 mg. Hoffmann et al5 stated that patients who already had significantly worsened hearing are more likely to develop further decrease of the hearing threshold. Kaasinen et al7 reports 2 deaf ears after injection of only 30 mg of gentamicin, Murofushi et al9 after
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60 mg. This indicates that there is no safe amount of gentamicin, although it is evident that low doses should be used. The application of 1 single dose is now recommended in some publications.18,19 It is also not known how much gentamicin gets lost through the Eustachian tube and never passes the round window membrane. Some otolaryngologists give advice that the head should be turned with the affected side down during instillation. That way the loss of fluid through the eustachian tube should be avoided. The use of a continuous middle ear perfusion was thought suitable to ascertain to the lowest individual dose. Titration was halted when signs of vestibular affliction became evident. Küppers et al6 observed good vertigo control and no deaf ears in that way. Magnusson et al12 found that there was a delay between the administration of an ototoxic agent and its effect on the cochlea and the vestibular function. This suggests that during a continuous perfusion the adequate dose might be quickly exceeded unnoticed. Therefore, it is also likely that hospitalization time is extended unnecessarily. This stands in contrast to treatment on an outpatient base.3,4 We conclude that the continuous gentamicin perfusion is of no advantage over other applications in terms of effect on hearing and hospitalization time. With 60% of the patients having achieved a functional level of 2 or better, our results are comparable with those presented by Kerr and Toner.20 Sixty percent of their patients already selected for surgery improved after the authors had merely talked to them about surgery and had given them time to think about the procedure. For these 60%, an invasive procedure could be avoided. REFERENCES 1. Lange G. 27 Jahre Erfahrung mit der transtympanalen Aminoglycosid-Behandlung des Morbus Menière. Laryngol Rhinol Otol 1995;74:720-3. 2. Balyan FR, Teibah A, De Donato G, et al. Titration streptomycin therapy in Menière’s disease: long-term results. Otolaryngol Head Neck Surg 1998;118:261-6. 3. Driscoll CLW, Kasperbauer JL, Facer GW, et al. Low-dose intratympanic gentamicin and the treatment of Menière’s disease: preliminary results. Laryngoscope 1997;107:83-9.
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4. McFeely WJ, Singleton GT, Rodriguez FJ, et al. Intratympanic gentamicin treatment for Menière’s disease. Otolaryngol Head Neck Surg 1998;118:587-96. 5. Hoffmann F, Beck C, Beck C, et al. Subablative Gentamicintherapie bei M. Menière. HNO 1993;41:296-300. 6. Küppers P, Ahrens H, Blessing R. Die kontinuierliche intratympanale Gentamicininfusion beim Morbus Menière. HNO 1994;42:429-33. 7. Kaasinen S, Pyykkö I, Ishizaki H, et al. Intratympanic gentamicin in Menière’s disease. Acta Otolaryngol 1998;118:294-8. 8. Murofushi T, Halmagyi GM, Yavor RA. Intratympanic gentamicin in Menière’s disease: results of therapy. Am J Otol 1997;18:52-7. 9. Ödkvist LM, Bergholtz LM, Lundgren A. Topical Gentamycin treatment for disabling Menière’s disease. Acta Otolaryngol 1984;412(Suppl):74-6. 10. Sala T. Transtympanic gentamicin in the treatment of Menière’s disease. Auri Nasus Larynx 1997;24:239-46. 11. Corsten M, Marsan J, Schramm D, et al. Treatment of intractable Menière’s disease with intratympanic gentamicin: review of the University of Ottawa experience. J Otolaryngol 1997;26:361-4. 12. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Menière’s disease. Acta Otolaryngol 1991;111:671-6. 13. Pfleiderer AG. The current role of local intratympanic gentamicin therapy in the management of unilateral Menière’s disease. Clin Otolaryngol 1998;23:34-41. 14. AAO-HNS Committee on Hearing and Equilibrium. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. Otolaryngol Head Neck Surg 1995;113:181-5. 15. Mondain M, Mouchet F, Marlier F, et al. Labyrinthectomie chimique: résultats et intérêt. Ann Otolaryngol Chir Cervicofac 1998;115:234-42. 16. Rauch SD, Oas JG. Intratympanic gentamicin for treatment of intractable Menière’s disease: a preliminary report. Laryngoscope 1997;107:49-55. 17. Allison RS, Eizenmann M, Tomlinson RD, et al. Vestibulo-ocular reflex deficits to rapid head turns following intratympanic gentamicin instillation. J Vestib Res 1997;7:369-80. 18. Harner SG, Kasperbauer MD, Facer GW, et al. Transtympanic gentamicin for Menière’ syndrome. Laryngoscope 1998;108: 1446-9. 19. Lange G. Transtympanic injections facilitate gentamicin treatment for Menière’s disease. 4th international symposium on Menière’s disease, Paris 1999. 20. Kerr AG, Toner JG. A new approach to surgery for Menière’s disease: talking about surgery. Clin Otolaryngol 1998;23:263-4. 21. Lange G Technische Schwierigkeiten bei der intratympanalen gentamycintherapie des Morbus Menière. Laryngol Rhinol Otol 1985;64:174. 22. Nedzelski JM, Chiong CM, Fradet G, et al. Intratympanic Gentamicin instillation as treatment of unilateral Menière’s disease: update of an ongoing study. Am J Otol 1993;14:278-82.