Wandong She

Hearing evaluation of intratympanic methylprednisolone perfusion for refractory sudden sensorineural hearing loss

Objective: To investigate the effectiveness and safety of intratympanic methylprednisolone perfusion (IMP) through a microcatheter in patients with sudden sensorineural hearing loss (SSNHL) who failed a conventional treatment. Study Design: Prospective clinical study. Setting: This study was conducted in Nanjing Drum Tower Hospital, Nanjing University Medical School. Subjects and Methods: Patients who had failed a minimum 10-day conventional treatment were included. Twenty-six patients in the study group (SG) received methylprednisolone perfusion through a microcatheter placed into the tympanum once a day for 10 days and the conventional treatment. Twenty-three patients who received a second conventional treatment (no steroid) served as the comparison group (CG). All patients were followed up for three months after the end of treatment. Results: The effective rates for SG and CG were 50 percent (61.9% when only patients with an interval from onset to IMP ≤ 60 days were included) and 21.7 percent, respectively (χ2 = 4.194, P = 0.041). The pure-tone average improvement was 20.2 ± 15.6 dB in SG, and 9.2 ± 13.7 dB in CG (z = 2.51, P = 0.011). In SG, hearing improvement at low frequencies was better than that at high frequencies. The interval from onset to IMP affected the efficacy of IMP. Conclusion: IMP through a microcatheter is a promising treatment for refractory SSNHL. The data suggest that the treatment may be more effective when administered at the earlier stages of SSNHL when the conventional treatment has failed.

Relationship of Glucocorticoid Receptor Expression in Peripheral Blood Mononuclear Cells and the Cochlea of Guinea Pigs and Effects of Dexamethasone Administration

Background Glucocorticoids (GCs) are widely used to treat sudden sensorineural hearing loss (SSNHL) and significantly improve hearing. However, GC insensitivity has been observed in some patients of SSNHL. Objective To study the correlation between GR expression in peripheral blood mononuclear cells (PBMCs) and in the cochlea of guinea pigs at mRNA and protein levels. Methods One group of guinea pigs received dexamethasone (10 mg/kg/day) intraperitoneally for 7 consecutive days (dexamethasone group), and another group of guinea pigs received normal saline (control group). Real time PCR and Western blotting were used to detect the expression of GR mRNA and GR protein in PBMCs and the cochleae. Results The GR mRNA and GR protein were detected in both PBMCs and the cochlear tissue of guinea pigs. GR mRNA and GR protein levels in PBMCs were positively correlated with those in the cochlea. The expression of GR mRNA and GR protein was significantly increased in the dexamethasone group compared to the control group. Conclusions Levels of GR mRNA and GR protein in the PBMCs were positively correlated with those in the cochlea of guinea pigs. Systemic dexamethasone treatment can significantly up-regulate GR expression in PBMCs and in the cochlea. Measurement of the GR level in PBMCs could be used as an indicator of GR level in the cochlea.

Intratympanic methylprednisolone perfusion as a salvage treatment for profound idiopathic sudden sensorineural hearing loss.

OBJECTIVE This study aimed to examine the effectiveness of intratympanic methylprednisolone perfusion as salvage treatment for profound idiopathic sudden sensorineural hearing loss. METHODS A retrospective clinical study of 97 patients with unilateral profound idiopathic sudden sensorineural hearing loss was performed. In all, 83 patients who received salvage intratympanic methylprednisolone perfusion plus conventional treatment (except for steroids) as the second-line therapy were assigned to the study group, while 14 patients who received conventional treatment alone were assigned to the comparison group. RESULTS In the study group, treatments in patients with a shorter interval from disease onset to intratympanic methylprednisolone perfusion (up to 15 days) had significantly greater improvements in the overall effective rate and pure tone average compared with patients with a longer interval (over 15 days). For patients with a short interval from disease onset to intratympanic methylprednisolone perfusion, those in the study group had significantly greater improvements in the overall effective rate and pure tone average compared with those in the comparison group. In both the study and comparison groups, hearing improvements were greater at low frequencies than at medium and high frequencies. CONCLUSION The interval from disease onset to intratympanic methylprednisolone perfusion was the major factor affecting hearing recovery. Early second-line salvage intratympanic methylprednisolone perfusion significantly improved the degree of hearing recovery in profound idiopathic sudden sensorineural hearing loss patients after failure of systemic steroid treatment.

Histone Deacetylase 2 in Sudden Sensorineural Hearing Loss Patients in Response to Intratympanic Methylprednisolone Perfusion.

Objective To evaluate the expression of histone deacetylase 2 (HDAC2) in peripheral blood mononuclear cells (PBMCs) from patients with sudden sensorineural hearing loss (SSNHL) who were refractory to systemic glucocorticoid treatment and to identify the relationship between the level of HDAC2 and glucocorticoid insensitivity. Study Design Prospective clinical study. Setting This study was conducted in Nanjing Drum Tower Hospital, Nanjing University Medical School. Subjects and Methods PBMCs were collected from 42 refractory SSNHL patients. After a 10-day intratympanic methylprednisolone perfusion (IMP) and systemic Ginkgo biloba extract treatment, the SSNHL patients were divided into 2 groups according to their hearing recovery after IMP (IMP sensitive and insensitive). Real-time polymerase chain reaction and HDAC2 protein assays were used to detect the relative expression levels of HDAC2 in PBMCs. The HDAC2 mRNA expression and protein levels in PBMCs collected from 17 volunteers were used as normal HDAC2 reference levels. Results Compared with normal reference levels, HDAC2 protein levels were significantly reduced, while the HDAC2 mRNA expression was much higher in all refractory SSNHL patients before IMP. HDAC2 mRNA expression and HDAC2 protein levels were significantly elevated in the IMP-sensitive group, while no change was observed in the IMP-insensitive group after IMP plus systemic antioxidant treatment. Conclusions Reduced HDAC2 protein levels may be 1 of the mechanistic underpinnings of corticosteroid insensitivity in refractory SSNHL patients. IMP can increase HDAC2 protein levels and the expression of HDAC2 mRNA in IMP-sensitive patients. HDAC2 protein levels might be regulated through posttranslational modifications.

Small tympanic membrane perforations in the inferior quadrants do not impact the manubrium vibration in guinea pigs.

Background It has been believed that location of the perforation has a significant impact on hearing loss. However, recent studies have demonstrated that the perforation sites had no impact on hearing loss. We measured the velocity and pattern of the manubrium vibration in guinea pigs with intact and perforated eardrum using a laser Doppler vibrometer in order to determine the effects of different location perforations on the middle ear transfer functions. Methods Two bullas from 2 guinea pigs were used to determine stability of the umbo velocities, and 12 bullas from six guinea pigs to determine the effects of different location perforations on sound transmission. The manubrium velocity was measured at three points on the manubrium in the frequencies of 0.5–8 kHz before and after a perforation was made. The sites of perforations were in anterior-inferior (AI) quadrants of left ears and posterior-inferior (PI) quadrants of right ears. Results The manubrium vibration velocity losses were noticed in the perforated ears only below 1.5 kHz. The maximum velocity loss was about 7 dB at 500 Hz with the PI perforation. No significant difference in the velocity loss was found between AI and PI perforations. The average ratio of short process velocity to the umbo velocity was approximately 0.5 at all frequencies. No significant differences were found before and after perforation at all frequencies (p>0.05) except 7 kHz (p = 0.004) for both AI and PI perforations. Conclusions The manubrium vibration velocity losses from eardrum perforation were frequency-dependent and the largest losses occur at low frequencies. Manubrium velocity losses caused by small acute inferior perforations in guinea pigs have no significant impact on middle ear sound transmission at any frequency tested. The manubrium vibration axis may be perpendicular to the manubrium below 8 kHz in guinea pigs.

Aminophylline restores glucocorticoid sensitivity in a guinea pig model of sudden sensorineural hearing loss induced by lipopolysaccharide

Glucocorticoids have been used to treat hearing loss and vestibular dysfunction for many years. However, some reports have indicated that a subset of patients with these disorders exhibit glucocorticoid insensitivity or resistance. A reduction in histone deacetylase 2 (HDAC2) activity and expression has been reported to play a critical role in glucocorticoid resistance. Here, we investigated the protective effects of aminophylline on HDAC2 expression and glucocorticoid sensitivity in lipopolysaccharide (LPS)-induced sudden sensorineural hearing loss in guinea pigs. We assessed hearing recovery in LPS-applied guinea pigs, which were either left untreated or were systemically treated with either dexamethasone, aminophylline, or a combination of the two. We utilized fluorescence microscopy and enzyme-linked immunosorbent assay to analyze the distribution patterns of HDAC2 and detect its levels in the cochlea. We used hematoxylin-eosin staining to examine cochlear histopathological changes. In the absence of treatment, significant hearing loss was detected in LPS-exposed animals. A synergistic effect was observed between aminophylline and dexamethasone in maintaining HDAC2 expression levels, preventing hearing loss in LPS-exposed animals and reducing cochlear damage. This study indicates that aminophylline can restore glucocorticoid sensitivity, which provides a new approach to treating patients with hearing disorders who are refractory to glucocorticoids.

Hearing Efficacy of Intratympanic Methylprednisolone Perfusion for Severe and Profound Sudden Sensorineural Hearing Loss

Objectives: Investigate the efficacy of intratympanic methylprednisolone perfusion (IMP) for severe and profound sudden sensorineural hearing loss (SSNHL). Methods: Hearing recovery was analyzed retrospectively in SSNHL patients, who received IMP after not fully responding to conventional treatments and were hospitalized in our department between January 2008 and December 2012. Results: Eighty-seven patients with SSNHL were divided into 4 types according to primary hearing curve: total deafness (77.01%), mild to moderate hearing loss in all frequencies (18.39%), hearing loss in low-tone frequencies (2.30%), and hearing loss in high-tone frequencies (2.30%). The effective rate was 66.7% and average pure tone average (PTA) improvements were 18.53 ± 13.54 dB in the patients of interval from onset to IMP within 15 days, 21.2% and 5.92 ± 15.18 dB in the patients of interval between 16 and 30 days, 4.8% and 3.69 ± 7.00 dB in the patients of interval more than 30 days, respectively. The effective rate had significant differences among the 3 different interval groups (χ2 = 25.91, P = .000), and the PTA improvements in the patients of interval within 15 days were the best in the 3 groups (F = 11.182， P = .000). A total of 30 cases were responsive to IMP, one of them was hearing loss in low tone frequencies and the other 29 cases were in all frequencies. The average hearing improvements in the lower 3 frequencies (0.25 kHz-1 kHz)were better than those in the higher 3 frequencies (2 kHz-8 kHz; F = 9.494, P = .000). Conclusions: Receiving IMP earlier may help to improve hearing recovery for the patients with SSNHL not fully responding to conventional treatments. The hearing improvements in the lower frequencies may be better than those in the higher frequencies after IMP.

Expression of HDAC2 in Peripheral Blood Mononuclear Cells from Patients with Sudden Sensorineural Hearing Loss

Objectives: (1) Compare the expression of HDAC2 in peripheral blood mononuclear cells (PBMC) of refractory sudden sensorineural hearing loss (SSNHL) patients before and after intratympanic methylprednisolone perfusion (IMP). (2) Identify the relationship between the level of HDAC2 and the prognosis of patients. Methods: Twenty cases of refractory SSNHL patients were selected as therapy group and 10 volunteers were chosen as control group. All 20 SSNHL patients received one course of routine therapy or more, including GC, vasodilator, and neurotrophins. SSNHL patients-PBMCs were collected in the morning before and after IMP, while volunteers were collected on the second day in hospital from January 2013 to September 2013. After therapy, the 20 SSNHL patients were divided into 2 groups (GC sensitive group and GC insensitive group) according to their hearing recovery. Real-time polymerase chain reaction and HDAC2 Assay Kit were used to detect the expression level of HDAC2 mRNA and amount of HDAC2 protein in PBMCs. The data were analyzed with SPSS 17.0 software. Results: Before intratympanic methylprednisolone perfusion, the level of HDAC2 protein were significantly depressed in all SSNHL patients (F = 13.291,<.0001), while the HDAC2 mRNA expressing much higher than the control group (F = 6.047, =.007). The expression level of HDAC2 mRNA increased significantly after intratympanic methylprednisolone (GC sensitive group: t = 3.941, P = .006; GC insensitive group: t = 2.57, P = .026). The HDAC2 protein level in GC sensitive group increased significantly (t = 6.148, P < .001). Conclusions: Knockdown of HDAC2 expression induces corticosteroid insensitivity. Glucocorticoids can increase the expression of HDAC2 mRNA. HDAC2 can be down-regulated by posttranslational modifications.

Response to: Hearing evaluation of intratympanic methylprednisolone perfusion for refractory sudden sensorineural hearing loss, from Dong-Hee Lee

refractory SSNHL. If the time interval between onset and treatment is the most important factor in SSNHL and refractory SSNHL, I suggest that a second cycle of systemic steroid treatment, within a proper period from onset, may be helpful for patients with refractory SSNHL. Therefore, to confirm that IMP through a microcatheter is effective for refractory SSNHL, its results should be compared with those of a second cycle of systemic steroid treatment. Otherwise, the study only proves that a second cycle of steroid treatment, either systemically or locally administered, may be effective when administered at the earlier stages of refractory SSNHL. I recommend that the authors consider this in the future randomized control trial to examine the effectiveness of IMP in the treatment of refractory SSNHL. Dong-Hee Lee, MD Department of Otolaryngology–Head and Neck Surgery College of Medicine The Catholic University of Korea Seoul, Korea E-mail, leedh0814@catholic.ac.kr