INTRA-TYMPANIC DEXAMETHASONE INJECTIONS: ARE THEY EFFECTIVE FOR LONG-TERM CONTROL OF VERTIGO?
Introduction
Menière’s disease (MD), characterized by recurrent attacks of vertigo, fluctuating hearing loss (HL) and tinnitus, is a common disease with an incidence of 15–50 per 100,000 population.1 Intractable MD was referred to a group of patients who are strongly prevented from participating in activities of daily life and interacting with their social environment, due to frequent attacks of vertigo, especially with progressive sensorineural HL, despite various kinds of medical and psychological management.2
Since McCabe’s original description of autoimmune HL,3 clinical and laboratorial evidence continues to suggest that MD may be an immune-mediated disorder. The findings of auto-immune response to type-II collagen,4 elevated levels of IgG circulating immune complexes,5–7 focal inflammation with intraepithelial invasion by mononuclear cells recognized as ‘endolymphatic sacitis’ by Danckwardt-Lilliestrom,8 and the demonstration of auto-antibodies to the endolymphatic sac9 suggest that auto-immunity plays a major role in the pathophysiology of MD.
This theory of immune involvement has led to the widespread use of steroids as a first-line treatment for MD.1 Detection of corticosteroid receptors within the inner ear and histological changes to stria vascularis by corticosteroids have evidenced a crucial role of steroids in the inner-ear physiology.
Lohius et al.11 demonstrated that the cellular structure of the stria vascularis underwent atrophy after removal of adrenal steroids, and Rarey12 has showed that it returned to normal after administration of corti-costeroids. As results of these advances, steroids are being used in MD in order to control this immunologi-cal reaction. Systemic steroid administration has been proved successful and is one of the current standard treatment options. Oral and intravenous steroid treatment, although very easy to use, has well-known side effects in the long term. According to Nadel13 these side effects include high susceptibility to infection, diabetes, osteoporosis, peptic ulcer, glucoma, impaired wound healing, myopathy, hypertension, psychological changes, and avascular necrosis of the femoral head. Therefore, they must be used very cautiously and only when there is absolute necessity. Intra-tympanic (IT) therapy for MD has evolved since the introduction of ‘titration protocols’ for IT gentamicin.14 The success of such intermittent injections of gentamicin inevitably has led to a similar use of IT steroids. Chandrasekhar15 demonstrated a significantly higher concentration of dexamethasone in the perilymph after its injection intra-tympanically in a guinea pig model than its level after intravenous dexamethasone. Parnes16 reported evidence that corticosteroids accumulate in inner ear fluids in much larger concentrations and remain longer after round window perfusion in guinea pig than after oral or intravenous administration. Hamid17 found high concentrations of dexamethasone in the inner ear liquids with minimal diffusion to the blood. Dexamethasone is one of the most potent corticosteroids, is the longest acting and causes the least sodium retention.18 After this encouraging findings, it seems reasonable that IT therapy with dexamethasone avoids the side effects associated with systemic steroids, treats only the affected ear, and results in increased level of corticosteroids in the inner ear.
Our current study was constructed to investigate the efficacy of intra-tympanic dexamethasone injection in the form of one single course of injections with or without repeated injections if needed on the long-term control of vertigo and hearing loss in patients with intractable unilateral definite MD.
A prospective, two-year follow-up study was carried out in the department of ORL & HNS of Tanta University Hospitals, Egypt between January 2008 and November 2011, to assess the efficacy of IT dexamethasone 4 mg/ml on patients with intractable unilateral definite MD. During the study period, 32 patients with a clinical diagnosis of intractable MD were eligible for participating in our clinical trial. The following inclusion criteria were fulfilled by our study group: 1) patients older than 21 years of age; 2) Definite unilateral MD as defined by the 1995 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines;19 3) Intact tympanic membrane; 4) No intake of oral corticosteroids in the last six months before injection; 5) No previous history of surgery for MD or for chronic suppurative otitis media; 6) Failure of various forms of medical treatment to control the intractable vertigo for at least six months prior to the study; and 7) Pure tone audiometry scores (PTA) better than 70 dB HL.
For eligible patients, a detailed explanation of the study, including risks, complications, and possible benefits was provided and after that a written informed consent was obtained. The present study was approved by the Ethical Review Board of our Faculty of Medicine. Our study group was subjected to thorough history taking to assess their vertiginous spells as regards onset, frequency, duration and severity, in addition to subjective HL, tinnitus and aural fullness during the last six months prior to the IT injection. Afterwards, patients were subjected to general physical evaluation and a complete ear, nose and throat examination. Audiometric evaluation was performed prior to the procedure and during each post-procedure follow-up visit. We used a pure-tone average (PTA) of 0.5, 1, 2 and 4 kHz, because these were the standard frequencies tested in our department. Speech discrimination scores (SDSs) were also recorded.
We used the worst audiogram during the six months prior to the injection as our pre-operative audiogram, while the worst audiogram during the last six months of the follow-up period was considered our postoperative audiogram. A change of ten dB or more in PTA, or 15% or more of SDS as defined by 1995 AAO-HNS, guidelines was considered clinically significant.
Procedure
With the patient supine on a stretcher in the office with the head turned 45 oC to the opposite side and the neck fully extended, an Emla cream (Lidocaine 2.5%/ Prilocaine 2–5%, Astra Zeneca Pharmaceuticals) was applied to regionally anesthetize the TM in the antero-superior quadrant of the involved ear. Before injection, one needle hole was made in the anesthetized area for air to escape, followed by another second hole through which dexamethasone in a dose of four mg/ml was injected slowly into the middle ear space using a 25-gauge spinal needle attached to one ml tuberculin-type syringe. The amount injected ranged from 0.4 to 0.6 ml (average 0.5 ml). After the injection, patients were kept supine for 20–30 minutes with the treated ear up and asked not to swallow and stay still. If the initial injection was too uncomfortable, lidocaine 1% without epinephrine was added to subsequent injections at a ratio of 0.1 to 0.9 ml of dexamethasone. The injections were repeated on the next day, and then given weekly for three consecutive weeks. Our protocol entails a total of 5 IT dexamethasone injections in a month. Patients in our study were seen for evaluation and progress notes at three, six, 12, 18 and 24 months intervals. During the study, some cases required reinjection procedures in the form of single or multiple injections if the disease decompensates again (reappearance of the vertiginous spells), or has not shown complete resolution.
Complications, if any, were recorded during the follow-up visits.
All the data from treatment results were processed statistically with the use of SPSS, version 16. We used the mean, standard deviation and chi-square test. The unpaired student t test was used to compare PTAs and SDSS. A p value ≤ 0.05 was assigned for significance.
Results
Thirty-two patients met our inclusion criteria. Eighteen were men and 14 were women. The average age of patients was 46.65 ± 11.1 (26–65 years). IT injections were delivered in 22 right ears and ten left ears. The average duration of illness before treatment was 7.63 ± 2.6 (six months-13 years). Twenty patients (63%) were stage 3, ten patients (31%) stage 2 and only two patients (6%) were stage 1.
At the end of the two-year follow-up, complete control (Class A) was achieved in 17 patients (53%), and a substantial control (Class B) in seven patients (22%), which means the number of patients who had satisfactory relief or vertigo was 75%. No patient was worse than before treatment. Re-injections in the form of one to a maximum of four were given to seven cases of those who got class A and all seven patients of class B. Before treatment, 97% of our patients were classified as functional levels 3 and 4 (56% and 41% respectively). At the end of the follow-up period, functional level 1 was achieved by 17 patients (53%) and level 2 by 12 patients (38%), with only three patients (9%) having level 1.
During the six months before the treatment, the mean number of vertigo spells per month was 1.47 ± 0.84 (0.2–4). During the follow-up visits, the mean was reduced significantly and reached 0.24 ± 0.32 (0–1) at the end of the two years ( p = 0.001).
Hearing results
At the end of the follow-up period, eight patients had improvement of their hearing by ten dB or more while only two patients showed deterioration of their hearing by ten dB, and 22 patients stayed the same. The mean pre-injection PTA was 45.71 dB (SD = 0.14), and the mean post-procedure PTA was 41.34 dB (SD = 13.87). The difference was statistically significant (p = 0.009). The mean improvement in speech discrimination for the entire group was 1.4%, not quite reaching significance (p = 0.55). Along the follow-up duration (two years), none of our patients showed relevant post-treatment complications. No cases of acute otitis media, dead ear or residual perforation were reported.
Discussion
IT steroid injection provides the potential for a near-direct application of corticosteroids to the area of immune dysfunction because the round window has been shown to be permeable to corticosteroids.16
The overall improvement of vertigo which was achieved in 75% of our patients with intractable MD (53% complete relief and 22% substantial control) which was sustained for two years, according to 1995 AAO-HNS reporting guidelines, is the most important finding in our study. Our goal would not have been achieved successfully without shifting to the intermittent (as needed) policy of repeated injections. This regiment entails IT dexamethasone injection upon recurrence of vertigo or patients’ unease with their symptoms.
This and other research has sparked interest in dealing with this mode of therapy which carries the corti-costeroids directly to the inner ear. Sakata first investigated this therapeutic alternative for MD in 1987, and along with Itoh,20 reported relief of vertigo in 78% and improvement of tinnitus in 74% in their 61 patients after IT dexamethasone injection. None of their patients felt any deleterious side effects. Shea and Ge21 found 96% relief of vertigo at one year and 76% at two years of follow up. Sennaroglu et al.22 found 17 patients (72%) to have satisfactory relief for their intractable vertigo (42% complete and 30% substantial) when used topical dexamethasone through a ventilation tube. Barrs23 demonstrated complete control of vertigo in 52% at three months and in 43% at six months. Repeated injections in five patients who had initial control, but later failed, yielded control in three of them. Garduno-Anaya et al.18 reported 100% improvement of vertigo (82% complete and 18% substantial) in his dexamethasone group after two years follow up. Hearing was improved in 35%. Boleas-Aguiree et al.24 have used a Kaplan-Meier time to event statistical method and found that dexamethasone injections were effective in controlling vertigo in 91% of their patients. Repeated injections were needed in more than 50% of the study group during the two-year follow-up. The results of Herraiz et al.25 confirmed the efficacy of IT steroid in control of MD symptoms. After 24 months, the number of vertigo spells was reduced from 4.3 to 0.5; tinnitus relief was achieved in 82% of the patients, and the average improvement in PTA was 8.6 dB. Re-injections of vertigo control were required by 35% of their patients.
Although vertigo control remains the most important goal of treatment in patients with intractable MD, there is also a concomitant interest in the treatment of hearing loss and/or preventing the progressive impairment which usually associates with the disease.
The literature to date is divided, with some articles suggesting improvement and others showing no significant change in the disease course. Shea and Geo21 initially reported an early 70% improvement, which was later decreased to 35% in patients with long-term follow-up. Silverstein et al.26 reported that hearing improved in 29% of patients treated in a similar way. Other reports, however, call into question the real efficacy of steroids on hearing. Silverstein updated his original observations with a report on the results of a group of 20 patients with stage-IV MD27, and concluded that IT steroids injected by his protocol did not significantly improve hearing in patients with MD. Arriaga and Goldman28 reported on 15 patients and their conclusion was that a single intratympanic steroid injection did not significantly improve hearing in patients with MD.
With the evaluation of the changes in hearing levels obtained throughout our study, we found eight patients (25%) to have a decrease of ten dB or more in their PTA, and only two patients showing deterioration of hearing by the end of the follow-up period. This statistically significant beneficial effect was observed at the 12-months follow-up visit and the maximum benefit was obtained at the two-years visit.
Our results confirm the efficacy of IT steroids in the control of MD symptoms. This success can be explained to some extent by the anti-inflammatory and immunosuppressive action of the dexamethasone on the immunological abnormalities in MD. Another explanation is the adoption of the intermittent (as needed) policy for those who showed failures or those who felt unease with their symptoms. It is unlikely that patients in our series persist with these repeated injections of IT steroids if they do not consider them to have a positive impact on their symptoms. On the other hand, the failure which has been detected in some of our cases with intractable MD during and at the end of follow-up period could be attributed to two reasons: 1) The pathophysiology of their disease does not belong to the immune theory with presence of other factors which share in its eruption; 2) The presence of mucosal bands or fibrous adhesions around or overlying the round window membrane, as Silverstein29 had found that the round window was partially (17%) or completely covered with obstructing membranes in patients with otherwise normal middle ears.
Quaranta,30 Green31 and Silverstein32 found vertigo improvement in 74% at seven years of follow up, 78% at 14 years, and 71% at 8.3 years respectively. Based on the results of these articles, it cannot be claimed that the success achieved was simply placebo or just the result of the natural history of fluctuation of symptoms in MD.
The high initial response, in addition to the successful long-term resolution seen at the end of the two-year follow up, the significant improvement of hearing, and the absence of complications would seem to give credence to the use of dexamethasone in a dose of four mg/ml given as needed IT injections for cases of intractable MD.
We recommend adopting this regimen as an effective monotherapy in the form of when needed IT injections for those patients who did not find a permanent resolution of their symptoms after a single course of injection.
Conclusion
Our data suggest a definitive role for the use of IT steroids in the treatment of intractable unilateral Menière’s disease. At a dose of 4 mg/mL of dexamethasone in the inner ear perfusion therapy by a single course of intratympanic injections given over 3 weeks coupled with repeated injections in some patients, we obtained a complete control of vertigo in 53% of the patients at the end of the follow-up period.
The IT steroid injection of dexamethasone four mg/mL is a promising alternative to more invasive or destructive surgical procedures for patients with intractable MD.
The IT steroid injection is a safe in-office procedure, avoids the side effects that are associated with the use of systemic steroids or aggravation of another pre-existing medical condition, treats only the affected ear, avoids a possible effect on the contralateral normal inner ear, has a better profile and higher concentrations in the perilymph and endolymph than the systemic use, and also has the possibility of avoidance of a more invasive surgical procedure and the costs related to that procedure.
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Address for correspondence: Prof. Abobakr Behery, Department of Otorhinolaryngology, Tanta University Hospitals, Tanta, Egypt. behery_ent@hotmail.com
Cholesteatoma and Ear Surgery – An Update, pp. 243–247
Edited by Haruo Takahashi
2013 © Kugler Publications, Amsterdam, The Netherlands