Abstract
INTRODUCTION:
Meniere’s disease is a common chronic inner ear disease. Because the definitive pathogenesis is still unknown, there is currently no cure for this disorder. Semicircular canal plugging (SCP), first used to treat patients with intractable benign paroxysmal positional vertigo, has since been applied to patients with intractable peripheral vertigo. This study was aimed to explore the long-term efficacy of triple semicircular canal plugging (TSCP) in the treatment of intractable Meniere’s disease (MD) so as to provide a new method in the framework of treatment with MD.
METHODS:
Three hundred and sixty-one unilateral MD patients, who were treated with TSCP in our hospital between Dec. 2010 and Sep. 2016, were recruited in this study for retrospective analysis. Vertigo control and auditory function were monitored during a period of two-year follow-up. Seventy three patients who were subjected to intratympanic gentamicin were selected as a control group. Pure tone audiometry, caloric test, vestibular evoked myogenic potential (VEMP) were performed in two-year follow-up.
RESULTS:
The total control rate of vertigo in TSCP group was 97.8% (353/361) in the two-year follow-up, with complete control rate of 80.3% (290/361) and substantial control rate of 17.5% (63/361). The rate of hearing loss was 26.3% (95/361). The total control rate of vertigo in intratympanic gentamicin group was 83.6% (61/73), with complete control rate of 63.0% (46/73) and substantial control rate of 20.5% (15/73). The rate of hearing loss was 24.7% (18/73). The vertigo control rate of TSCP was significantly higher than that of chemical labyrinthectomy(χ2 = 24.798, p < 0.05). There was no significant difference of hearing loss rate between two groups. (χ2 = 0.087, p > 0.05).
CONCLUSION:
Triple semicircular canal plugging (TSCP), which can reduce vertiginous symptoms in patients with intractable Meniere’s disease (MD), represents an effective therapy for this disorder. It might become a new important method in the framework of treatment with MD.
Introduction
Meniere’s disease is a common chronic inner ear disease, which is characterised by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and aural pressure. It has been documented that the prevalence ranges from 3.5 to 513 per 100,000, with the most current estimate at approximately 2 per 1000 [3]. Because the definitive pathogenesis is still unknown, there is currently no cure for this disorder. Due to the overlapped menifestations with other episodic vertigo diseases such as vestibular migraine, misdiagnosis was common in clinical practice. Medical treatment should be considered for all patients initially, and four fifths of patients can be free from these symptoms. Betahistine and diuretics are most widely used drug for Meniere’s disease. However, the newest report of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial showed that current evidence is limited as to whether betahistine prevents vertigo attacks caused by Meniere’s disease, compared with placebo [2]. Operative measures such as endolymphatic sac surgery, vestibular neurectomy and labyrinthectomy are considered when medical treatment fails to control the vertigo. As a conservative operation, endolymphatic sac surgery was often used in intractable MD patients, but, the rate of vertigo control was only 60% 80% and the benefit of this procedure is controversial and might be related to a placebo effect due to some reports [4, 25]. Yet Welling et al reported that the original data of the Thomsen-Bretlau placebo-controlled study on sac surgery actually revealed a significant therapeutic benefit of the sac surgery over placebo [23]. So sac surgery is still widely used to treat intractable MD patients until now. Although vestibular neurectomy has a very high rate of vertigo control, the risk of operation is high [22]. Labyrinthectomy, undertaken as a last resort, is only reserved for patients with total deafness [20].
Intratympanic gentamicin, widely used as a minimally invasive outpatient procedure for refractory Ménière’s disease, reduces vertigo, but inevitably impairs the function of the hair cell of vestibular end organs and more worryingly, in up to 20% of cases, hearing function also deteriorates [18]. Another drawback to gentamicin therapy was that the dose of gentamicin to inject, the frequency of injections, the number of doses to give, and clinical endpoints for therapy are still not well understood.
Steroid injection is a non-ablative and safe treatment for refractory Ménière’s disease. Intratympanic dexamethasone injection has been used by several investigators to control symptoms of vertigo and hearing loss in patients with Meniere’s disease. In a 2-year prospective placebo-controlled double-blinded randomised trial, Garduno-Anaya and colleagues [9] studied the effect of dexamethasone perfusion of the inner ear in patients with unilateral Meniere’s disease. They concluded that dexamethasone at 4 g/L injected into the ear transtympanically showed an 82% complete control of vertigo compared with 57% control in the placebo group. A recent double-blind comparative effectiveness trial reported that the mean number of vertigo attacks in the final 6 months compared with the 6 months before the first injection decreased 90% in the methylprednisolone group [16]. Although intratympanic dexamethasone injection has some improvements in tinnitus, hearing loss, and aural fullness, the vertigo control rate is lower compared with surgery, so it is often used as a treatment before surgery step in the internationally recommended guidelines [13, 20].
Semicircular canal plugging (SCP), first used to treat patients with intractable benign paroxysmal positional vertigo, has since been applied to patients with intractable peripheral vertigo [15]. Charpiot et al reported that the control rate of vertigo was 75% in 28 patients with MD underwent lateral canal plugging [6]. Yin et al used triple semicircular canal occlusion to treat only three patients with MD who underwent unsuccessful endolymphatic sac decompression or mastoid shunt, finding that two cases had complete control of vertigo and the other had substantial control [24]. In our previous study, we had reported the results of a cohort of 79 patients who accepted TSCP as the first surgical intervention. The vertigo control rate was excellent as 98.7% (78/79) in two-year follow-up, with complete control rate of 81.0% (64/79) and substantial control rate of 17.7% (14/79), though there was 29.1% patients had hearing loss [26]. Until now, over 500 cases of TSCP had been performed in our clinical practice and 361 patients had been followed up more than two years. The present study was designed to evaluate long-term efficacy of TSCP for these 361 patients and compare the effects between TSCP and intratympanic gentamicin.
Materials and methods
Patients
From Dec. 2010 to Sep. 2016, 361 MD patients (177 men, 184 women; age 29–68 years, mean 51.8) with full clinical documents in vertigo clinic of Shandong Provincial ENT Hospital, Shandong University were included in this study for retrospective analysis. All patients received a clinical diagnosis of definite Meniere’s disease according to the American Academy of Head and Neck Surgery (AAO-HNS) criteria in 1995 [1] and accepted TSCP surgery. All the patients had unserviceable hearing (PTA threshold >60 dB or speech recognition rate <50%). All patients were given the standardized conservative treatment which comprised Betahistine 12 mg tid and Hydrochlorothiazide 25 mg bid at least six months. Even after the aforementioned therapy, vertigo still occurred at least 2 attacks once a month and each attack lasted more than 20 minutes, suggesting that vertigo was not controlled effectively in all patients. Cerebello-pontine angle tumors were excluded by MRI and patients with possible bilateral Meniere’s disease who had bilateral fluctuating tinnitus and hearing loss with vertigo were excluded. Main outcome measurements consisted of vertigo control and auditory function. Baseline and 2-year follow-up data were obtained during the patient examination. Pure-tone audiometry, caloric test and VEMP were performed for evaluation of audiological and vestibular function before surgery and 2 years after surgery. This was a retrospective study. Seventy-three patients (35 men, 38 women; age range 27–70 years, mean 51.2) who accepted intratympanic gentamicin (26.7 mg/mL) given weekly for up to two injections during the same period were selected as a comparison group. All patients received a clinical diagnosis of definite Meniere’s disease according to the American Academy of Head and Neck Surgery (AAO-HNS) criteria in 1995 [1] and were also given the standardized conservative treatment which comprised Betahistine 12 mg tid and Hydrochlorothiazide 25 mg bid at least one year. All the patients also had unserviceable hearing (PTA threshold >60 dB or speech recognition rate <50%).
The study was approved by the Ethics Committee of Shandong University and written informed consents were obtained from all subjects.
Surgical procedure of TSCP
The procedure had been reported on our previous study [26]. Briefly speaking, the surgery was performed under general anesthesia by postauricular approach. Three bony semicircular canals were exposed through mastoidectomy. The bone was drilled up to the “blueline” in the central portion of the bony canal. A 2-mm segment of canal was skeletonized to create a fenestra, without opening either the endosteum or the membranous labyrinth. A plug of temporalis fascia was inserted through the fenestra to compress the endosteum and membranous labyrinth close against the back bony wall. The fenestration was covered with bone wax to prevent perilymphorrhea. The incision was closed and the operation was over.
Intratympanic gentamicin
Intratympanic injections were done in outpatient clinics. One phial of Gentamicin sulfate (80 mg/2 ml) was first diluted with 1 ml of 5% NaHCO3. One milliliter of this solution, corresponding to 26.7 mg of gentamicin, was then injected in the postero-inferior portion of the tympanic membrane of the affected side upon topical anesthesia with a 2.5% Lidocaine, under microscopic view and with the aid of a spinal needle. The patient was placed supine with the head rotated 45° contralaterally in respect to the ear to be treated and kept in this position for 30 min after the injection. Two injections were given, the second injection one week after the first.
Evaluation of vertigo
A definitive spell of vertigo lasting more than 20 min was regarded as a Meniere’s vertigo attack according to the AAO-HNS criteria issued in 1995 [1]. Patients were instructed to record acute attacks of vertigo, coexisting symptoms (such as tinnitus, aural fullness, changes in hearing) and other characteristics included time of onset and duration in a paper based diary for the full 24 month study duration. The frequency of definite vertigo attacks 6 months before treatment was compared with the frequency of attacks occurring between 18 and 24 months after treatment. The vertigo control after 2 years was established using the formula and criteria of the AAO-HNS and noted on a scale of A (complete control) to F (no control, secondary treatment). Patients with scale A (complete control) and B (substantial control) were defined as successful vertigo control.
Evaluation of hearing
Hearing function was measured by a pure tone audiometer and was evaluated based on the four-tone average formulated by (a + b+c+d)/4 (a, b, c and d are hearing levels at 0.5 kHz,1 kHz, 2 kHz and 3 kHz, respectively) according to 1995 AAO-HNS criteria [1]. The worst hearing level during the 6 months of the surgical ear before treatment has been compared with the worst hearing level between 18 and 24 months after treatment. Changes greater than 10 dB in hearing level is “better” or “worse” and changes within 0–10 dB is “no change”. Changes greater than 20 dB in hearing level is “profound”.
Caloric test
The bithermal caloric test was performed according to Fitzgerald and Hallpike. Each ear was irrigated alternatively with a constant flow of air at 24 °C and 49 °C for 40 seconds. The response was recorded over 3 minutes, and a 7-minute interval between each stimulus was respected to avoid cumulative effects. A video-based system was used (Ulmer VNG, v. 1.4; SYNAPSYS, Marseille, France) to acquire and analyze the eye response. The maximum slow-phase velocity (SPV) of nystagmus after each irrigation was calculated and, unilateral weakness (UW) was determined according to Jongkee’s formula. In our laboratory, the value of UW less than 20% was considered to be normal. The value of UW more than 90% was considered to be canal paresis.
VEMP test
From 2010 to 2013, only cVEMP was tested. From 2014 to 2016, both cVEMP and oVEMP were all tested.
From 2010 to 2013, cVEMPs were recorded using a Smart EP device (Intelligent Hearing Systems, USA). The electromyographic activity of the sternocleidomastoid muscle was recorded while patients were laying supine on a bed and asked to raise their head off of the bed in order to activate their neck flexors bilaterally and the saccular receptor were acoustically stimulated with air-conducted acoustic stimulation. The recording electrode was placed at the middle third of the muscle ipsilateral to the stimulated ear, the reference electrode was placed on the upper edge of the sternum and the ground electrode was placed on the sternocleidomastoid muscle contralateral to the stimulated side. Attention was paid to place bilateral electrodes on symmetrical site. The amplifier gain was set to 100,000, and signals and bandpass were filtered 10 to 3000 Hz. Short-tone bursts (100 dB nHL, 500 Hz, each, with 1 ms raise fall time and 5-ms plateau time) were delivered monaurally by TDH 49P earphones. The stimulation rate was 5 Hz; the analysis time was 60 ms. A total of 128 responses to stimuli were averaged, and measurements were repeated twice to check test wave reproducibility. We analyzed the amplitudes of the first positive-negative peak, p13-n23 and peak latencies of p13 and n23. The average of two runs was taken for the amplitudes and latencies. The amplitude ratio between the two ears over 1.61 was considered abnormal. The latency of p13 over 17.3 ms, while, n23 over 24.6 ms was considered abnormal.
From 2014 to 2016, the recording system of VEMPs was using the Neuro-Audio auditory evoked potential equipment (Neurosoft LTD, Ivanov, Russia). The test was performed with the patients in the seated position. Narrow band Chirp and tone burst stimuli were delivered via a standard insert earphone (ER-3A). Active reecording electrodes with respect to the cVEMP examination were placed on the region of the upper third of the sternocleidomastoid muscle (SCM) on both sides. The reference electrodes were placed on the upper sternum. The ground electrode was on the nasion. The head was rotated towards the contralateral side of the stimulated ear to achieve tonic contraction of the SCM during recording. For the oVEMP, active recording electrodes were placed on the infra-orbital ridge 1 cm below the center of each lower eyelid and reference electrodes were positioned approximately 1 cm below them. The ground electrode was on the nasion. oVEMP were recorded with eyes open and maximal gaze upwards. The electrode impedance was maintained below 5kΩ and the stimulation rate was 5.1 Hz. The VEMPs were measured with 500 Hz tone burst and the initial intensity was 110 dB nHL. The intensity decreased from 110 dB nHL to the threshold in 5 dB steps. cVEMP superimposition number n is 60 times, oVEMP superimposition number 100≤n≤200, analysis time is 0–50 ms. Bandpass filtering of cVEMP is 30–2000 Hz and bandpass filtering of oVEMP is 1–1000 Hz. The latency of p1 over 17.3 ms, while, n1 over 24.6 ms of cVEMP was considered abnormal. The amplitude ratio over 30% was considered abnormal. The latency of n1 over 12.6 ms, while, p1 over 17.8 ms of oVEMP was considered abnormal. The amplitude ratio over 30% was considered abnormal.
Statistics
χ2 test was used to compare the vertigo control rate and hearing loss rate between patients with TSCP surgery and patients with intratympanic gentamicin. χ2 test was used to compare the abnormal rate of VEMP test pre- and post-operatively in TSCP and intratympanic gentamicin patients. P < 0.05 was considered significant.
Results
The total control rate of vertigo in TSCP group was 97.8% (353/361) in the two-year follow-up, with complete control rate of 80.3% (290/361) and substantial control rate of 17.5% (63/361). The rate of hearing loss and profound hearing loss was 26.3% (95/361) and 10.0% (36/361) respectively. The total control rate of vertigo in intratympanic gentamicin group was 83.6% (61/73), with complete control rate of 63.0% (46/73) and substantial control rate of 20.5% (15/73). The rate of hearing loss and profound hearing loss was 24.7% (18/73) and 9.6% (7/73). The vertigo control rate of TSCP was significantly higher than that of chemical labyrinthectomy (χ2 = 24.798, p < 0.05) (Table 1). There was no significant difference of hearing loss rate between two groups. (χ2 = 0.087, p > 0.05) (Table 2). The age, gender, hearing level and duration of disease of patients with TSCP had no significant with that of patients with intratympanic gentamicin (p > 0.05) (Table 3).
The control rate of vertigo in TSCP and intratympanic gentamicin patients
The control rate of vertigo in TSCP and intratympanic gentamicin patients
The hearing loss rate in TSCP and intratympanic gentamicin patients
Clinical characteristics in TSCP and intratympanic gentamicin patients
In TSCP group, 219 patients (60.7%) had abnormal caloric test presenting a poor response in affected side prior to operation. Twenty-four months after treatment, canal paresis was found in the operation side of all patients by means of caloric test. 361 patients all had cVEMP tests. 187 patients (51.8%) were abnormal in cVEMP with a decreased amplitude in the affected ear preoperatively. The proportion turned to be 54.8% (198/361) postoperatively, which had no significant difference compared with the results detected preoperatively (χ2 = 0.673, p > 0.05) (Table 4). Only 282 patients had done oVEMP tests. 156 patients (55.3%) were abnormal in oVEMP with a decreased amplitude in the affected ear. The proportion turned to be 59.6% (168/282) postoperatively, which had no significant difference compared with the results detected preoperatively (χ2 = 0.806, p > 0.05) (Table 5).
Abnormal rate of cVEMP pre- and post-operatively in TSCP and intratympanic gentamicin patients
Abnormal rate of oVEMP pre- and post-operatively in TSCP and intratympanic gentamicin patients
In intratympanic gentamicin group, 42 patients (57.5%) had abnormal caloric test presenting a poor response in affected side prior to operation. Twenty-four months after treatment, canal paresis was found in the operation side of 60 patients (82.2%) by means of caloric test. 38 patients (52.1%) were abnormal in cVEMP with a decreased amplitude in affect ear. cVEMP presented 94.5% abnormally postoperatively, which had significant difference compared with the results detected preoperatively (χ2 = 33.622, p < 0.05) (Table 4). 37 patients (50.7%) were abnormal in oVEMP with a decreased amplitude in affect ear. oVEMP presented 80.8% abnormally postoperatively, which had significant difference compared with the results detected preoperatively (χ2 = 14.722, p < 0.05) (Table 5).
Post-operatively, TSCP group suffered from temporary vertigo and imbalance. All patients had spontaneous nystagmus immediately postoperatively. Vertigo resolved in all patients within 5 days, while imbalance resolved with an average recovery time of 15.4 days. No patients had facial paralysis, cerebrospinal fluid leakage, and other complications.
Although there is currently no cure for MD, more than 85% of patients with these disorders are benefited from either changes in lifestyle or medical treatment. Operative measures are considered when conservative treatment has failed to control the vertigo. In addition with traditional surgical methods, semicircular canal plugging has been reported to use to treat MD as a new method recently [6, 24].
In this work, we found that, in these 361 MD patients, who were initially treated with TSCP, the vertigo was controlled effectively in 97.8% of patients at two-year follow-up. The vertigo control rate of TSCP was much higher than that of intratympanic gentamicin in our study. Our results proved that TSCP could, indeed, control vertigo effectively in MD patients. Caloric test showed that the surgery induced a canal paresis in affected side in all patients, which indicated that TSCP could control vertigo by eliminating function of semicircular canal. The possible mechanism might be that when semicircular canal was plugged, endolymph fluid in this position is blocked, the movement of endolymph within a semicircular canal is greatly reduced, leading to minimal stimulation of hair cells during angular motion and change in endolymph pressure.
The present study found that the results of VEMP test were not significantly different from that pre- and post-TSCP, suggesting that TSCP had no damage on otolith organ. Thus, vestibular compensation might be built faster than labyrinthectomy or vestibular neurectomy. In this report, imbalance disappeared in most patients within 1–2 week after TSCP surgery. And due to our study, the time of imbalance duration in patients with labyrinthectomy or vestibular neurectomy was 30 days, which was longer than TSCP (Data not shown). Other study reported that cats which underwent TSCP recovered faster than cats which underwent labyrinthectomy [10]. Additionally, TSCP was reported to have no effect on resting discharge of vestibular end organ [19], which was beneficial to recovery of imbalance. In our research, we observed spontaneous nystagmus in all patients after surgery which lasted only for a few days. We might ascribe this phenomenon to the “quiescent stage” of the end organs whose resting discharge was affected temporarily, yet the resting discharge would recover in the long run as the end organs were morphologically undamaged. Moreover, histological samples from patients with recurrence who underwent labyrinthectomy for revision surgery showed no significant difference of end organ hair cells between TSCP patients and controls (Data was not shown in this paper).
Compared with TSCP, the processes of vestibular neurectomy and labrinthectomy are variable. It was reported that although some patients will compensate fully following ablative surgery, up to 30% may be left with considerable chronic disequilibrium or motion-provoked vertigo [11]. One study showed that even though most labyrinthectomy patients are relieved of vertigo, only 50% of them returned to work [17]. On the other hand, vestibular neurectomy has been shown to cause a longer delay before returning to work [8]. Findings from this work clearly reveal that TSCP, as a new inner ear surgery, has advantages compared with traditional surgeries in treating MD such as vestibular neurectomy or labrinthectomy. TSCP could preserve the function of utricle and saccule and the vestibular compensation was built faster.
Intratympanic gentamicin, widely used as a minimally invasive outpatient procedure for refractory Ménière’s disease, reduces vertigo, but inevitably impairs the function of the hair cell of vestibular end organs and more worryingly, in up to 20% of cases, hearing function also deteriorates [18]. Another drawback to gentamicin therapy was that the dose of gentamicin to inject, the frequency of injections, the number of doses to give, and clinical endpoints for therapy are still not well understood. The action of gentamicin in the inner ear has been investigated extensively. Gentamicin accumulates predominantly in type 1 vestibular hair cells and causes subsequent atrophy of these cells as well as the whole of the neuroepithelium [12]. Compared with intratympanic gentamicin, TSCP had limited damage to hair cells of semicircular canals and cochlea. It was just through blocking the movement of endolymph within semicircular canals to control vertigo. So, TSCP was less destructive compared with chemical labyrinthectomy theoretically. But if the patient also had vestibular function loss in another side, then oscillopsia might occurred in TSCP, which should be paid attention in clinic.
Our research found that about one fourth patients had hearing loss either in TSCP or intratympanic gentamicin group. So we preferred that TSCP and intratympanic gentamicin were used in those MD patients who had unserviceable hearing. In this study, all patients had unserviceable hearing before TSCP or intratympanic gentamicin. Flanagan et al reported 21.4% of hearing loss and 81.3% of vertigo control after a single injection of gentamicin, and Casani et al. reported 12% of hearing loss after a maximum of 2 injections of gentamicin, and 81% vertigo control [5, 7]. In our study, there was a 20.5% hearing loss and 83.6% vertigo control rate in intratympanic gentamicin group, which was mostly accordance with previous report. In TSCP group, the hearing loss rate was 26.4%, which was not significantly different with intratympanic gentamicin group. While the reason of hearing loss for TSCP was not clear, serous fibrous labyrinthitis or perilymphorrhea might be the cause [14].
Conclusion
In conclusion, TSCP shows definite long-term effects in the treatment of patients with intractable MD. TSCP changed the dilemma of traditional vertigo surgery. It obtained the excellent vertigo control effect which could comparable to vestibular neurectomy or labrinthectomy. The vertigo control rate of TSCP was much higher than that of intratympanic gentamicin. TSCP will, in deed, become a novel modality for intractable MD. It might be a new important method in the framework of treatment with MD.
Footnotes
Acknowledgments
This study was funded by National Natural Science Foundation of China (no. 81200744) and the Focus on research and development plan in Shandong province (no. 2018GSF121027), China.