Introduction
Idiopathic sudden sensorineural hearing loss (SNHL) is commonly defined as hearing loss of more than 30 dB over at least three contiguous frequencies, occurring over a period of up to three days.Reference Schreiber, Agrup, Haskard and Luxon 1 As the term idiopathic suggests, the aetiology and pathophysiology of idiopathic sudden SNHL are largely unknown. Possible causes include vascular compromise, viral infection and autoimmune disease.Reference Schreiber, Agrup, Haskard and Luxon 1 Owing to its possible multifactorial origin, various treatment protocols for improving hearing recovery in idiopathic sudden SNHL patients have been proposed. Since the double-blind clinical trial conducted by Wilson et al. in the early 1980s,Reference Wilson, Byl and Laird 2 systemic steroids have been widely accepted as a first-line treatment within these protocols. However, steroids can be directly applied to affected ears using an intratympanic approach, which has been used to treat various inner-ear disorders, including idiopathic sudden SNHL. Indeed, intratympanic steroids were initially used by Schuknecht to control vertigo in Ménière's disease in the 1950s.Reference Schuknecht 3 Animal experiments suggest that intratympanic steroid perfusion delivers a significantly higher steroid concentration to the perilymph, with lower or no systemic steroid absorption compared with systemic administration.Reference Chandrasekhar, Rubinstein, Kwartler, Gatz, Connelly and Huang 4 , Reference Parnes, Sun and Freeman 5 Intratympanic steroids are usually used in three treatment protocols for idiopathic sudden SNHL: (1) as an initial treatment without systemic steroidsReference Tsai, Hsueh, Huang and Lin 6 , Reference Filipo, Covelli, Balsamo and Attanasio 7 ; (2) as an adjunct treatment concomitant with systemic steroidsReference Battaglia, Burchette and Cueva 8 , Reference Ahn, Yoo, Yoon and Chung 9 ; and (3) as a salvage treatment after failure of systemic steroids.Reference Ho, Lin and Shu 10 – Reference Moon, Lee, Kim, Hong and Lee 13 Salvage intratympanic steroid perfusion has been used to treat idiopathic sudden SNHL in Nanjing Drum Tower Hospital since 2007.Reference She, Dai, Du, Yu, Chen and Wang 14
Dexamethasone and methylprednisolone are the steroids most commonly used for intratympanic delivery. Although both have anti-inflammatory effects on the cochlea, Parnes and colleagues reported that methylprednisolone reaches a higher concentration and is present for longer than dexamethasone in the perilymph and endolymph.Reference Parnes, Sun and Freeman 5 In addition, Trune and Kempton demonstrated that methylprednisolone can also regulate sodium transport or/and reabsorption in the cochlea, which is important for the cochlear function, but that dexamethasone may not.Reference Trune and Kempton 15 Based on these reports, methylprednisolone was selected for intratympanic perfusion in the present study.
The World Health Organization classification of hearing impairment defines profound idiopathic sudden SNHL as a pure tone average (PTA) of more than 80 dB at 0.5, 1.0, 2.0 and 4.0 kHz.Reference Mathers, Smith and Concha 16 The disease has a relatively poor prognosis and a poor response to initial systemic steroid treatment. 17 , Reference Edizer, Çelebi, Hamit, Baki and Yiğit 18 Most patients who received salvage intratympanic methylprednisolone perfusion after failure of initial systemic steroids at the Department of Otolaryngology – Head and Neck Surgery, Nanjing Drum Tower Hospital, had been diagnosed with profound idiopathic sudden SNHL. To determine the efficacy of salvage intratympanic methylprednisolone perfusion for profound idiopathic sudden SNHL, the present study reviewed and analysed clinical data from all profound idiopathic sudden SNHL patients treated in Department of Otolaryngology – Head and Neck Surgery from April 2007 to January 2015.
Materials and methods
Patient groups
All protocols used in the present study were approved by the Ethics Committee of Nanjing Drum Tower Hospital and complied with their ethical standards on human experimentation. Data were collected from the medical records for all hospitalised unilateral profound idiopathic sudden SNHL patients (PTA ≥ 81 dB at 0.5–4 kHz) in the Department of Otolaryngology – Head and Neck Surgery between April 2007 and January 2015.
Within a week of disease onset, all patients had received first-line conventional treatment for at least 10 days. After failure of the first-line treatment, patients received second-line treatment comprising either a second 10-day regimen of conventional treatment (comprising vasodilators and thrombolytic anticoagulant) or intratympanic methylprednisolone perfusion plus conventional treatment (comprising vasodilators and thrombolytic anticoagulant). These treatments were administered as previously reported.Reference She, Dai, Du, Yu, Chen and Wang 14 , Reference Hou, She, Du, Dai, Xie and Zhou 19 PTA findings at 0.25–8.0 kHz were used to evaluate hearing levels. A PTA gain of less than 15 dB was defined as failure of the first-line treatment.
For second-line treatments, patients in the study group received intratympanic methylprednisolone perfusion plus conventional treatment, while patients in the comparison group received a second round of conventional treatment only.
Hearing assessment and follow up
Hearing was assessed by pure tone audiometry after disease onset, before and after first-line conventional treatment and second-line treatment, and at three months after the second treatment. Hearing thresholds were recorded as the maximum output value plus 5 dB if the patient had no response to the maximum audiometric output. All data were collected and recorded by the same clinician.
The change in PTA (i.e. PTA after onset minus PTA at three months after treatment) was used to evaluate hearing outcome. A final PTA of within 10 dB of the hearing level in the contralateral ear was defined as complete hearing recovery. Significant, partial and no recovery were defined as changes in the PTA of at least 30, 15–29 and less than 15 dB, respectively. Complete, significant and partial recovery were considered effective outcomes and used for calculating the overall effective rate.
Statistical analysis
Data were analysed using IBM SPSS Statistics software version 19.0 (Armonk, New York, USA) and expressed as means ± standard deviation (SD). Data from patient groups were compared using the Student's t-test or the Mann–Whitney U-test. The Mann–Whitney U-test was used for non-normally distributed data. Qualitative data were analysed using the χ2 test. A p value less than 0.05 was considered statistically significant.
Results
Clinical characteristics of the study and comparison groups
A total of 97 patients with profound idiopathic sudden SNHL were included in the study: 83 were assigned to the study group and 14 to the comparison group. There were no significant differences in sex, average age, ear laterality, or the presence of dizziness or tinnitus between the study and comparison groups. However, there were significant between-group differences in the mean initial PTA values (i.e. after disease onset) and the interval from disease onset to second-line treatment. Hearing loss after disease onset was slightly greater in the comparison group than in the study group (p = 0.047), while the interval from disease onset to second-line treatment was significantly longer in the study group than in the comparison group (p = 0.000; Table I).
Table I Study and comparison groups: general clinical characteristics and therapeutic effects
Data are means ± standard deviation. *Pearson χ2 test. †Independent-samples t-test. ‡Fisher's exact test. **Mann–Whitney U-test. SG = study group; CG = comparison group; M = male; F = female; y = years; L = left; R = right; PTA = pure tone average; d = days; ΔPTA = change in pure tone average
Although significant hearing improvement at three months after second-line treatment was recorded in most patients in the study group, there was no significant difference in the overall effective rate or in PTA improvement between the study and comparison groups (p = 0.066 and p = 0.053, respectively; Table I). In this preliminary analysis, all patients in the study group were compared with all patients in the comparison group. However, this simple approach could not fully evaluate the therapeutic effects of salvage intratympanic methylprednisolone perfusion on profound idiopathic sudden SNHL. A more detailed analysis identified a significantly longer interval from disease onset to second-line treatment in the study group than in the comparison group (Table I). Patients in the study group had varying intervals from disease onset to intratympanic methylprednisolone perfusion and were therefore classified into three subgroups according to interval length: up to 15 days, 16–30 days and over 30 days. The overall effective rates at three months after two treatment courses in the comparison group and the three study subgroups are listed in Table II.
Table II Study and comparison groups: hearing recovery
Data are n. *Interval between disease onset to second-line treatment: short, up to 15 days; medium, 16–30 days; long, at least 31 days. †See main text for definitions. SG = study group; CG = comparison group
Effect on hearing recovery of interval length from disease onset to intratympanic methylprednisolone perfusion
For analysing the impact of interval length on hearing recovery, the study group was classified into two subgroups according to interval length: an interval from disease onset to intratympanic methylprednisolone perfusion of up to 15 days (shorter interval) was recorded in 39 patients and an interval of more than 15 days (longer interval) was recorded in 44 patients. There was no significant difference between these subgroups regarding sex, average age, ear laterality, presence of dizziness or tinnitus, initial PTA, or the PTA after first-line treatment. However, there were significant differences in both the overall effective rate and the change in PTA between subgroups. Patients with shorter intervals showed a significantly greater improvement in the overall effective rate and a significantly greater PTA change after all treatments (p Overall effective rate = 0.000, p PTA improvement = 0.008; Table III).
Table III Study group: effect of intratympanic methylprednisolone perfusion treatment interval on hearing recovery
Data are means ± standard deviation. *Pearson χ2 test. †Independent-samples t-test. ‡Fisher's exact test. M = male; F = female; y = years; L = left; R = right; PTA = pure tone average
Outcomes of second-line treatments in patients with shorter treatment intervals in the study and comparison groups
Since the mean interval from disease onset to second-line treatment was significantly longer in the study group than in the comparison group, hearing outcomes were compared in patients who had a short treatment interval (up to 15 days). No significant statistical differences in the initial PTA and in the PTA after first-line conventional treatment were found between patient subgroups (p > 0.05 for both). However, improvements in the overall effective rate and in the PTA after second-line treatment were significantly greater for patients in the study group than for those in the comparison group (p = 0.006 for both; Table IV).
Table IV Study and comparison groups: PTA before second line treatment and change after second line treatment for a short treatment interval
Data are means ± standard deviation. *Independent-samples t-test. †Pearson χ2 test. SG = study group; CG = comparison group; PTA = pure tone average; PTA = pure tone average
Effects of PTA improvement after first-line conventional treatment on final hearing recovery in the study group
Although all 39 patients with a short treatment interval (up to 15 days) in the study group had significantly better hearing recovery after second-line therapy, a detailed analysis revealed that these patients had different responses to first-line treatment. Of these, 24 patients with PTA improvements of 15 dB or more at three months after all treatments were assigned to the effective study subgroup, while the other 15 patients with PTA improvements of less than 15 dB were assigned to the ineffective study subgroup. Although there was no statistical difference in the initial PTA between these subgroups, hearing recovery after first-line treatment was better in the effective study subgroup (p = 0.024; Table V).
Table V Study group: pure tone average improvement after first-line conventional treatment
Data are means ± SD. *Independent-samples t-test. †Mann–Whitney U-test. ESG = effective study subgroup; ISG = ineffective study subgroup; PTA = pure tone average
Comparisons of pure-tone improvement at different frequencies
Patients in the study and comparison groups had similar responses to second-line treatment at different frequencies. In the study group, the mean (± SD) improvement in PTA after second-line treatment at low (0.25 and 0.5 kHz), medium (1.0 and 2.0 kHz) and high (4.0 and 8.0 kHz) frequencies were 21.30 ± 19.66, 14.52 ± 18.37 and 9.46 ± 14.26 dB, respectively. Hearing recovery was significantly different at the three frequency ranges: hearing improvement at low frequencies was greater than that at medium frequencies, and hearing improvement at the medium frequency range was better than at high frequencies (Figure 1).
Fig. 1 Graph showing the pure tone average (PTA) improvement at different frequencies in the study group. Data are means ± standard deviation. *p < 0.01.
In the comparison group, mean (± SD) improvement in PTA after the second-line conventional treatment at low, medium and high frequencies were 12.14 ± 19.63, 5.71 ± 11.74 and 2.14 ± 6.27 dB, respectively. The difference in hearing improvement was significant between the low and medium frequencies but not between the medium frequencies and high frequencies (Figure 2).
Fig. 2 Graph showing the pure tone average (PTA) improvement at different frequencies in the comparison group. Data are means ± standard deviation. **p < 0.05, ***p > 0.05.
Discussion
Although vascular compromise, viral infection and autoimmune diseases may be involved in the aetiology of idiopathic sudden SNHL, direct causes are thought to be thrombosis and embolism of the cochlear artery or spiral modiolar artery.Reference Michel 20 Based on these theoretical causes, thrombolytics, Ginkgo biloba and systemic steroids were recommended as treatments for profound idiopathic sudden SNHL by a Chinese multicentre clinical study group for idiopathic sudden SNHL and by the German Society of Otorhinolaryngology – Head and Neck Surgery. 17 , Reference Michel 20 However, patients with profound idiopathic sudden SNHL have a relatively poor response to this first-line treatment programme and exhibit high morbidity. Intratympanic steroid perfusion has been recommended as salvage treatment for idiopathic sudden SNHL by the American Academy of Otolaryngology Head and Neck Surgery since 2012.Reference Stachler, Chandrasekhar, Archer, Rosenfeld, Schwartz and Barrs 21 In line with these recommendations, thrombolytics, G biloba and systemic steroids comprised the first-line conventional treatment and intratympanic methylprednisolone perfusion was second-line salvage treatment in the present study.
The interval from idiopathic sudden SNHL onset to treatment is regarded as the most important factor affecting hearing outcome. In the present study, most patients in the study group had a long treatment interval (more than 15 days) from disease onset to intratympanic methylprednisolone perfusion, while all patients in the comparison group had a short interval (up to 15 days) from disease onset to the second-line treatment. To exclude the influence of interval length on the analysis, hearing outcomes were only compared between patients with a similar treatment interval (up to 15 days). These patients had a similar initial PTA at disease onset, but those who underwent salvage intratympanic methylprednisolone perfusion within 15 days of disease onset had much better hearing recovery compared with those who did not.
To investigate the benefits of prompt intratympanic methylprednisolone perfusion, therapeutic outcomes were compared between patients with shorter and longer treatment intervals in the study group. As expected, the overall effective rate and degree of PTA improvement were better in patients with a shorter treatment interval. Therefore, early intratympanic methylprednisolone perfusion plus conventional treatment is strongly recommended for profound idiopathic sudden SNHL patients for whom the conventional treatment regimen has failed. The administration of higher steroid concentrations in the cochlea via early intratympanic methylprednisolone perfusion may help prevent the development of irreversible auditory pathological changes. Banerjee and Parnes demonstrated significantly better hearing improvement in patients treated with intratympanic steroids within 10 days of idiopathic sudden SNHL onset compared with those treated after 10 days.Reference Banerjee and Parnes 22 However, some patients have shown a positive response to delayed intratympanic methylprednisolone injectionsReference Belhassen and Saliba 11 ; a similar response was observed in the present study. A female profound idiopathic sudden SNHL patient who did not respond to systemic steroids and received combined intratympanic methylprednisolone perfusion and conventional treatment 36 days after disease onset had completely recovered three months after intratympanic methylprednisolone perfusion. Therefore, delayed treatment incorporating intratympanic methylprednisolone perfusion can also be effective.
In the present study, patients with a higher PTA gain after first-line conventional treatment had significantly better hearing recovery at the final follow up. Therefore, greater hearing gain after first-line treatment may help predict the prognosis after intratympanic methylprednisolone perfusion. Consistent with this observation, Ito and colleagues reported a time-course of hearing improvement in idiopathic sudden SNHL patients, demonstrating that the hearing improvement rate at 1–2 weeks after treatment could predict their long-term prognosis.Reference Ito, Fuse, Yokota, Watanabe, Inamura and Gon 23 For this reason, a combination of intratympanic methylprednisolone perfusion and conventional therapy is strongly recommended for patients with greater hearing gain after first-line treatment.
A spontaneous hearing recovery rate of 30–60 per cent within two weeks of idiopathic sudden SNHL onset regardless of medical treatment has been reported.Reference Plaza and Herráiz 24 – Reference Piccirillo 27 However, spontaneous improvement was also reported to be rare in patients with severe-to-profound hearing loss.Reference Rauch 28 In the present study, all patients had profound hearing loss. Therefore, a hearing gain after the first-line treatments is unlikely to be due to spontaneous recovery: other factors, such as sensitivity to steroids, may also contribute to initial hearing recovery. A greater hearing gain after first-line systemic steroid treatment suggests higher sensitivity to steroids and thus a better response to intratympanic methylprednisolone perfusion.Reference She, Dai, Du, Yu, Chen and Wang 14 , Reference Hou, She, Du, Dai, Xie and Zhou 19 Intratympanic methylprednisolone perfusion effectively increases intra-cochlear steroid concentrations, improves cochlear blood flow,Reference Shirwany, Seidman and Tang 29 protects the inner ear from inflammation and maintains cochlear ion gradients,Reference Fukushima, Kitahara, Uno, Fuse, Doi and Kubo 30 resulting in greater hearing recovery.
Theoretically, intratympanic perfusion should yield a higher steroid concentration in the basal turn than in the apical turn of the cochlea.Reference Plontke, Biegner, Kammerer, Delabar and Salt 31 Consequently, hearing improvement should be better within the high frequency region. However, regardless of the treatment strategy, hearing improvement was better at the low frequencies in the present study. Similarly, better hearing recovery at low frequencies was previously reported for idiopathic sudden SNHL patients after salvage intratympanic perfusion.Reference Belhassen and Saliba 11 This result may be explained by the basal turn of the cochlea being more vulnerable to free radical damage and basal turn injuries being more difficult to treat compared with those in the apical turn.Reference Sha, Taylor, Forge and Schacht 32 , Reference Billett, Thorne and Gavin 33
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• The efficacy of salvage intratympanic methylprednisolone perfusion for profound idiopathic sudden sensorineural hearing loss was investigated
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• Early salvage intratympanic methylprednisolone perfusion may improve hearing recovery after systemic steroid failure
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• Greater hearing gain after first-line systemic steroids predicts a better prognosis after salvage intratympanic methylprednisolone perfusion
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• All patients had better hearing improvement at low frequencies regardless of the second-line therapy
In the present study, prompt salvage intratympanic methylprednisolone perfusion after failure of first-line systemic steroid treatment significantly improved hearing outcomes in profound idiopathic sudden SNHL patients. Intratympanic steroid administration is likely to achieve higher local concentrations in the inner ear without systemic side effects. However, disadvantages include possible ineffectiveness against systemic inflammatory disorders if inflammation extends beyond the inner ear. Moreover, the round window niche could be obstructed by pseudomembranes, which may impede steroid diffusion into the inner ear.Reference Alzamil and Linthicum 34 As there is evidence for the efficacy of both systemic and intratympanic steroids, a combination of the two treatment strategies (i.e. first-line systemic steroids and early intratympanic steroids if the initial treatment fails) should be considered to maximise anti-inflammatory effects inside and outside the inner ear.
In the present study, far fewer patients were included in the comparison group than in the study group because most patients preferred to undergo combined intratympanic methylprednisolone perfusion and conventional treatment after failure of first-line treatment. Thus, an imbalance in the sample sizes of study and comparison groups was a limitation of the present study. Long-term or multicentre studies are needed to overcome this problem.
Conclusion
Early intratympanic methylprednisolone perfusion combined with a conventional treatment regimen without systemic steroids may improve final hearing recovery in profound idiopathic sudden SNHL patients after failure of systemic steroid treatment. A greater PTA gain after first-line systemic steroid treatment may indicate a better prognosis for hearing after second-line treatment. Regardless of the second-line treatment strategy, hearing recovery was better at low frequencies than at medium and high frequencies.
Acknowledgements
The authors would like to thank Dr H Zhu for assistance with the statistical analysis and Drs M West and X Du for their invaluable comments in preparing the manuscript. This work was supported by the National Natural Science Foundation of China (W She, grant number 81271074); the Medical Science and Technology Development Foundation of Nanjing Department of Health (Y Dai, grant number YKK13054), the Clinical Medicine Foundation of the Science and Technology Department of Jiangsu Province, China (W She, grant number BL2014002), the Six-Talent Projects of Jiangsu Province, China (W She, grant number WSN-009), and an International Joint Research grant from the Science and Technology Department of Nanjing Jiangsu Province, China (W She, grant number 2012 sd311038).
