Intratympanic Injection Research Articles

A phase 1 clinical trial of DB-020 intratympanic injections administered prior to high dose cisplatin chemotherapy to reduce ototoxicity.

6043 Background: Hearing loss with cisplatin (CP) chemotherapy is common. DB-020 is a formulation of thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. The primary objective of this Phase 1 study was to evaluate the safety and tolerability of repeated IT injections of DB-020. A secondary objective was to compare hearing changes with DB-020 vs. placebo. Methods: Subjects scheduled for at least 3 cycles of CP and cumulative exposure of ≥280 mg/m2 were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other, once every 3 or 4 weeks, up to 3 hours before receiving CP. Subjects with moderate or severe hearing loss at baseline were excluded. Ototoxicity was defined by American Speech-Language-Hearing criteria: ≥20 dB threshold increase at any one test frequency, or ≥10 dB threshold increase in any two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously obtained. Severe ototoxicity was ≥20 dB threshold increase in any two adjacent frequencies. A pre-specified interim analysis evaluated safety, ototoxicity (with Mcnemar’s test using the last observation carried forward), and average threshold shifts (from air conduction audiometry, analyzed with a mixed model with repeated measures). Results: Nineteen subjects were randomized, with mean age of 57 years (84% male and 100% white) and mean cumulative CP dose 248 mg/m2. Most (95%) had head and neck cancers (5% had lung cancer). Seventeen subjects had both baseline and follow-up audiometry, and 16/17 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels were similar to reference values. Ear pain (15/19 subjects, 78.9%) and tinnitus (8/19 subjects, 42.1%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus was more common in placebo treated ears. There were no tympanic perforations, no serious adverse events in the category of ear and labyrinth disorders, and no deaths. Ototoxicity was significantly more common and more severe in placebo treated ears (Table). As the overall study objectives were met at this interim analysis, no further enrollment was pursued. Conclusions: In this initial clinical trial experience there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in cisplatin ototoxicity. These results warrant further clinical development. Clinical trial information: NCT04262336 . [Table: see text]

The impact of labyrinthine magnetic resonance signal alterations on the treatment of sudden sensory-neural hearing loss

Background Sudden sensory-neural hearing loss (SSNHL), with positive findings on magnetic resonance imaging (MRI), possibly related to labyrinthine hemorrhage, is a rare condition and difficult to be diagnosed. Objectives We evaluated the role of MRI in detecting labyrinthine signal changes and the impact of these changes on the prognosis of SSNHL after the intratympanic corticosteroid injection. Methods A prospective study was held between January and June 2022. We included patients who complained of SSNHL, either idiopathic (30 patients) or labyrinthine signal alterations (14 patients), as diagnosed by MRI performed 15 days after the SSNHL onset. In addition, all patients underwent a course of intratympanic prednisolone injections. Results 83.3% of the idiopathic group showed a complete or marked improvement after the intratympanic injection. Conversely, most cases of positive MR signal alterations (92.8%) had slight or poor improvement after the therapeutic course. Conclusions Our study revealed that MRI imaging is essential for assessing any SSNHL case. It can diagnose labyrinthine hemorrhage, whose course and prognosis differ significantly from idiopathic SSNHL. Significance Intratympanic prednisolone injection was effective in managing idiopathic SSNHL. On the other hand, this therapeutic modality was ineffective in improving SSNHL associated with labyrinthine hemorrhage.

Discriminant Analysis of the Prognostic Factors for Hearing Outcomes in Patients with Idiopathic Sudden Sensorineural Hearing Loss.

This study aims to determine and assess prognostic variables that might affect the hearing result in patients with idiopathic sudden sensorineural hearing loss following intratympanic steroid injection. In total, 190 patients with idiopathic sudden sensorineural hearing loss received intratympanic steroid injection. Two hearing indices (recovery and nonrecovery) will be analyzed as dependent variables; patient's age, time period between the onset of hearing loss and treatment, initial level of hearing (hearing loss pre), type of audiogram curve (upsloping, downsloping, and flat), presence of vertigo, presence of tinnitus, and diabetes) will be analyzed as prognostic factor variables. Recovery was seen in 72% of the patients. Different preinjection audiogram curves and hearing grades had a significant effect on recovery, absence of vestibular symptoms and no diabetic history were noted to have a good prognosis. Delay in treatment by more than 30 days from the onset of hearing loss was associated with a worse prognosis. Idiopathic sudden sensorineural hearing loss associated with late treatment plan more than 1 month, presence of vertigo, diabetes, and profound prehearing loss were negative prognostic factors. Whereas age, gender, and presence of tinnitus did not affect prognosis. More stable response was obtained when intratympanic steroids were added within 1 month after diagnosis, and the patient presented with mild or moderate hearing loss grade, flat or downsloping pure tone audiometery curve, and absence of vertigo and nondiabetic with significantly good results.

Low-Molecular-Weight Hyaluronic Acid Contributes to Noise-Induced Cochlear Inflammation

Introduction: Our previous work indicated that the activation of the Toll-like receptor (TLR) 4 signaling pathway contributed to noise-induced cochlear inflammation. Previous studies have reported that low-molecular-weight hyaluronic acid (LMW-HA) accumulates during aseptic trauma and promotes inflammation by activating the TLR4 signaling pathway. We hypothesized that LMW-HA or enzymes synthesizing or degrading HA might be involved in noise-induced cochlear inflammation. Methods: The present study included two arms. The first arm was the noise exposure study, in which TLR4, proinflammatory cytokines, HA, hyaluronic acid synthases (HASs), and hyaluronidases (HYALs) in the cochlea as well as auditory brainstem response (ABR) thresholds were measured before and after noise exposure. The second arm was analysis of HA delivery-induced reactions, in which control solution, high-molecular-weight HA (HMW-HA), or LMW-HA was delivered into the cochlea by cochleostomy or intratympanic injection. Then, the ABR threshold and cochlear inflammation were measured. Results: After noise exposure, the expression of TLR4, proinflammatory cytokines, HAS1, and HAS3 in the cochlea significantly increased over the 3rd to 7th day post-noise exposure (PE3, PE7). The expression of HYAL2 and HYAL3 dramatically decreased immediately after noise exposure, gradually increased thereafter to levels significantly greater than the preexposure level on PE3, and then rapidly returned to the preexposure level on PE7. The expression of HA, HAS2, and HYAL1 in the cochlea remained unchanged after exposure. After cochleostomy or intratympanic injection, both the hearing threshold shifts and the expression of TLR4, TNF-α, and IL-1β in the cochleae of the LMW-HA group were obviously greater than those of the control group and HMW-HA group. The expression of proinflammatory cytokines in the LMW-HA and control groups on the 7th day (D7) after cochleostomy tended to increase compared to that on the 3rd day (D3), whereas levels in the HMW-HA group tended to decrease on D7 compared to D3. Conclusion: HAS1, HAS3, HYAL2, and HYAL3 in the cochlea are involved in acoustic trauma-induced cochlear inflammation through the potential proinflammatory function of LMW-HA.

Menière's Syndrome Associated With Fibrous Dysplasia of the Temporal Bone.

Menière's Syndrome Associated With Fibrous Dysplasia of the Temporal Bone.

Assessment of drug permeability through an ex vivo porcine round window membrane model

Delivery of pharmaceutical therapeutics to the inner ear to treat and prevent hearing loss is challenging. Systemic delivery is not effective as only a small fraction of the therapeutic agent reaches the inner ear. Invasive surgeries to inject through the round window membrane (RWM) or cochleostomy may cause damage to the inner ear. An alternative approach is to administer drugs into the middle ear using an intratympanic injection, with the drugs primarily passing through the RWM to the inner ear. However, the RWM is a barrier, only permeable to a small number of molecules. To study and enhance the RWM permeability, we developed an exvivo porcine RWM model, similar in structure and thickness to the human RWM. The model is viable for days, and drug passage can be measured at multiple time points. This model provides a straightforward approach to developing effective and non-invasive delivery methods to the inner ear.

Treatment of Tinnitus with Intratympanic Injection of Dexamethasone Versus Oral Drugs.

Tinnitus is a symptom of cochlear dysfunction, which can disturb the patient emotionally and physically. As anxiety and tinnitus persist concurrently, certain benzodiazepines have been administered as possible tinnitus treatment options. In addition to pharmacological medications, certain studies have looked at the use of vitamins to treat tinnitus. Intratympanic steroids have been successfully used in various studies as well, for the treatment of tinnitus. A clinical based interventional study was taken up among the patients visiting the ENT OPD of a State Medical College and Hospital. 160 subjects were included in the study by convenient sampling method, taking the inclusion and the exclusion criteria into consideration. Out of them, 80 subjects were given an intratympanic injection of dexamethasone and rest 80 were given oral drugs like alprazolam and vitamin B complex. Among the patients who were treated with intratympanic dexamethasone, significant improvement was seen in 36 of them, with a p value of 0.00 as compared to those who were given oral drugs, in which only 10 showed improvement, with a p value of 0.32. The improvement of the symptoms is significantly related with the duration of the symptoms in our study. Patients presenting with severe SNHL was the commonest presentation but had the least improvement (29.6%). Patients presenting within one year of occurrence of the symptoms had maximum improvement. Intratympanic dexamethasone can be considered as a good alternative for improvement of symptoms of tinnitus.

Hearing loss and COVID-19: an umbrella review.

COVID-19 can result in an extensive range of extrapulmonary, and neurological signs and symptoms such as olfactory and/or taste dysfunction, and otologic symptoms. The aim of this study was to investigate the hearing loss manifestation from COVID-19. The goal of this umbrella review was to examine hearing loss associated with COVID-19 disease. English literature published until October 15, 2022 in online databases including PubMed, Scopus, Web of Science, and Embase was considered for this purpose. Eligibility of the articles for subsequent data extraction was evaluated in a two-step selection process with consideration to an inclusion/exclusion criterion. This review followed the PRISMA protocol and the Amstar-2 checklist for quality assessment. A total of four treatment strategies were used by different studies which included oral corticosteroids, intratympanic corticosteroids, combined oral and intratympanic corticosteroids, and hyperbaric oxygen therapy. Five studies investigated corticosteroid use in the forms of oral or intratympanic injection; four studies reported (complete or partial) hearing improvements after steroid treatment, while one study stated no significant improvement in hearing function. One study reported that oral corticosteroid monotherapy alone was not effective, while vestibular symptoms were ameliorated by a combination of oral prednisone, intratympanic dexamethasone injection, and hydroxychloroquine. The findings suggest that despite being one of the rare complications of COVID-19, hearing loss can impact a patient's quality of life. The most common type reported was sensorineural hearing loss, which can be diagnosed with variable techniques.

Efficacy of intratympanic or postauricular subperiosteal corticosteroid injection combined with systemic corticosteroid in the treatment of sudden sensorineural hearing loss: A prospective randomized study.

This study aimed to investigate the efficacy and safety of intratympanic or postauricular subperiosteal glucocorticoid injection combined with systemic glucocorticoid in the treatment of sudden sensorineural hearing loss (SSNHL). This study is a prospective randomized controlled study. This study included unilateral SSNHL patients who were hospitalized in our department between January 2020 and June 2021. Patients were randomly divided into three groups (groups A, B, and C). Patients in group A were treated with an intratympanic corticosteroid injection combined with systemic corticosteroid treatment, and patients in group B received a postauricular corticosteroid injection combined with systemic corticosteroid treatment. Patients in group C (control group) were treated with systemic corticosteroid alone. The case number of groups A, B, and C was 311, 375, and 369, respectively. There was no significant difference in gender distribution, the proportion of left and right affected ears, and the average interval from onset to treatment among the three groups (P > 0.05). However, there were significant differences in their average age, distribution of audiogram type, and hearing loss levels among them (P < 0.01). Our study shows that there was no significant difference in average hearing threshold improvement before and after treatment in the three groups (P > 0.05). Regarding the complications, in group A, 33 patients (10.6%) had a transient vertigo attack during tympanic injection, which lasted for ~1-3 min. In group B, 20 patients (6.43%) complained of pain at the injection site, which disappeared after 1-3 days. No other complications occurred in all the other patients. The addition of intratympanic or postauricular corticosteroid to systemic steroids did not result in a significant effect on hearing recovery in SSNHL. No obvious complications occur in SSNHL patients treated with intratympanic injection or postauricular injection of corticosteroid. [chictr.org.cn], registration number: ChiCTR2100048762.

Binocular 3-D otolith-ocular reflexes: responses of chinchillas to natural and prosthetic stimulation after ototoxic injury and vestibular implantation.

The otolith end organs inform the brain about gravitational and linear accelerations, driving the otolith-ocular reflex (OOR) to stabilize the eyes during translational motion (e.g., moving forward without rotating) and head tilt with respect to gravity. We previously characterized OOR responses of normal chinchillas to whole body tilt and translation and to prosthetic electrical stimulation targeting the utricle and saccule via electrodes implanted in otherwise normal ears. Here we extend that work to examine OOR responses to tilt and translation stimuli after unilateral intratympanic gentamicin injection and to natural/mechanical and prosthetic/electrical stimulation delivered separately or in combination to animals with bilateral vestibular hypofunction after right ear intratympanic gentamicin injection followed by surgical disruption of the left labyrinth at the time of electrode implantation. Unilateral intratympanic gentamicin injection decreased natural OOR response magnitude to about half of normal, without markedly changing OOR response direction or symmetry. Subsequent surgical disruption of the contralateral labyrinth at the time of electrode implantation surgery further decreased OOR magnitude during natural stimulation, consistent with bimodal-bilateral otolith end organ hypofunction (ototoxic on the right ear, surgical on the left ear). Delivery of pulse frequency- or pulse amplitude-modulated prosthetic/electrical stimulation targeting the left utricle and saccule in phase with whole body tilt and translation motion stimuli yielded responses closer to normal than the deficient OOR responses of those same animals in response to head tilt and translation alone.NEW & NOTEWORTHY Previous studies to expand the scope of prosthetic stimulation of the otolith end organs showed that selective stimulation of the utricle and saccule is possible. This article further defines those possibilities by characterizing a diseased animal model and subsequently studying its responses to electrical stimulation alone and in combination with mechanical motion. We show that we can partially restore responses to tilt and translation in animals with unilateral gentamicin ototoxic injury and contralateral surgical disruption.

Skull-vibration-induced nystagmus test in patients who are candidates for intratympanic gentamicin injection

This study aims to evaluate the utility of the skull-vibration-induced nystagmus test (SVINT) in the selection of patients with Ménière's disease (MD) for intratympanic injection of gentamicin. To date the indications for this treatment have been based only on subjective elements. A retrospective study was performed in 20 patients diagnosed with unilateral MD. SVINT were performed monthly and the evoked responses were evaluated. After 6 months, the results from patients who were candidates for gentamicin treatment (G group) were compared with those who did not need it (nG group). Correlation with Dizziness Handicap Inventory (DHI) score was evaluated. 120 tests were performed. Positive SVINTs were identified in 52 cases (43.3%) and included excitatory nystagmus in 18 (34.7%), inhibitory nystagmus in 28 (53.8%), and atypical pattern in 6 cases (11.5%). A significant increase excitatory nystagmus was recorded in group G (p = 0.00001). Moreover, there was a significant increase in the DHI score in group G compared with the nG group (p < 0.0001) and in patients with evoked excitatory nystagmus. The finding of excitatory nystagmus during SVINTs performed on several occasions in the follow-up prior to intratympanic injection of gentamicin strengthens this therapeutic choice.

Sudden Hearing Loss Related to COVID-19 Adenovirus Vector vaccine?

There are increasing reports connecting the coronavirus disease 2019 (COVID-19) vaccinations and adverse otological events. These events are mostly explained by the immunological effects or the recorded thrombotic consequences of the vaccinations. The inner ear is liable to be insulted by the thrombosis of the terminal auditory artery causing sudden sensorineural hearing loss (SSNHL). We reported two cases that suffered from SSNHL within 2 weeks after the first dose of the Oxford–AstraZeneca vaccine without any previous hearing problems. These cases showed severe–profound hearing loss in the audiological evaluation. The first case presented with a vestibular hypofunction in the affected ear and received a course of systemic corticosteroids, followed by anticoagulants (heparin). The second case, instead, received six intratympanic injections of corticosteroid, followed by hyperbaric oxygen therapy. The audiological function partially recovered after the treatment in both cases, with complete vertigo recovery in the first case. These results revealed a kind of similarity of the clinical course in COVID-19- and non-COVID-19-associated SSNHL. Hyperbaric therapy showed to be helpful for improving the prognosis.

Symptom: Vertigo After Labyrinthectomy

Symptom: Vertigo After Labyrinthectomy

Analysis of hearing prognosis risk factors in pediatric unilateral sudden sensorineural hearing loss

ObjectivesPediatric idiopathic sudden hearing loss (PISSNHL) is a rare disease with no established factor affecting its prognosis. In this study, we investigate the risk factors affecting the prognosis of PISSNHL. Material and methodsAmong the patients who visited our hospital from January 2010 to December 2021, the characteristics associated prognosis of 54 patients with unilateral PISSNHL were retrospectively confirmed. ResultsPatients' recovery was determined by applying Siegel's criteria (SC) and AAO-HNS criteria (AC). Twenty-seven (50 %) and 29 patients (54.3 %) recovered for SC and AC, respectively. Age, sex, side, duration between onset and treatment, administration of intra-tympanic steroid injection, accompanying symptoms (tinnitus and dizziness), BMI, serum creatinine level, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte count (PLR), lymphocyte count, and platelet count were not significantly different between the recovery group and the poor recovery group (P > 0.05). The patients were divided into five groups according to the initial hearing of the affected ear and again according to their audiogram type. The initial hearing levels, hearing level severity, and the audiogram type were significantly different between the deaf group (>100 dB HL) and the non-deaf group (P < 0.05). ConclusionThe prognosis of PISSNHL is closely related to the initial hearing at the onset. If the initial hearing level is <100 dB, the recovery rate is approximately 50 %, therefore requiring active treatment and emotional support. It may also be related to the type of audiometric curve.

Intratympanic steroid injection versus oral steroid as treatment of post COVID-19 Sudden sensorineural hearing loss (SSNHL)

Intratympanic steroid injection versus oral steroid as treatment of post COVID-19 Sudden sensorineural hearing loss (SSNHL)

Evaluation of Sudden Sensory-Neural Hearing Loss Patients Treated with Systemic Steroids with Additional Intratympanic Dexamethasone Injection in Different Intervals; a Clinical Trial Study.

The online version contains supplementary material available at 10.1007/s12070-023-03641-4.

Clinical Factors Associated With Prognosis of Tinnitus and Aural Fullness After Sudden Sensorineural Hearing Loss.

We evaluated the long-term prognosis and risk factors associated with tinnitus and aural fullness, which occurred with sudden sensorineural hearing loss. Retrospective cross-sectional review. Tertiary referral center. Those who visited our clinic for sudden hearing loss from January 2016 to May 2020, diagnosed with sudden sensorineural hearing loss based on pure-tone audiometry, and underwent magnetic resonance imaging to rule out other cause of hearing loss. In total, 106 patients were enrolled in this study. All patients were treated with oral glucocorticoids. Salvage intratympanic dexamethasone injection therapy was performed for the patients whose hearing was not fully recovered. We scored the loudness of tinnitus and the intensity of aural fullness using the numerical rating scale. We used a mixed-effects model for repeatedly measured tinnitus and aural fullness scores. The time after the onset of sudden sensorineural hearing loss (SSNHL; β = -0.07; 95% confidence interval, -0.09 to -0.05; p < 0.001) and hearing outcome after treatment (overall p = 0.003) were significant factors associated with the prognosis of tinnitus. Concerning aural fullness, the time after the onset of SSNHL was a significant prognosis factor ( β = -0.08; 95% confidence interval, -0.09 to -0.06; p < 0.001), unlike hearing outcome (overall p = 0.261). Pretreatment pure-tone audiometry average threshold and mainly affected frequencies were not significant factors for tinnitus and aural fullness recovery, respectively. The persistence of tinnitus with SSNHL was significantly affected by hearing recovery after treatment, whereas aural fullness was not associated with hearing recovery. However, both symptoms were improved over time after SSNHL.

A bibliometric and visualization study of Meniere's disease: Current status and global hotspots and emerging trends.

Meniere's disease (MD) is a clinical condition characterized by endolymphatic hydrops. Persistent symptoms negatively affect patients mood, and the underlying etiology remains unclear. It is necessary to comprehensively understand the relevant publications, review the history and current status of research, and analyze hotspots and frontiers of research on MD. We retrieved literature on Meniere's disease from 2003 to 2022 from the Web of Science database and extracted the data. Data visualization and analysis was conducted using Cite Space, VOS viewer, an online web tool, and Microsoft Office Power Point 2019. In total, 2847 publications were analyzed. The number of annual publications was relatively stable, with an accelerated upward trend over the past 5 years. The country with the most publications was USA (751, 26.38%), while the University of Munich contributed more publications than any other institution (117, 4.11%). The article titled "Diagnostic criteria for Meniere's disease" by Lopez-Escamez J et al in 2015 was the most cited and co-cited publication, and also had the top co-cited references with the strongest citation bursts. Naganawa S was the author with the most publications (85, 2.99%). The top 3 journals and co-cited journals were Otology Neurotology, Acta Oto Laryngologica, and Laryngoscope. Recently, the key theme words were "sensorineural hearing loss," "therapy," "intratympanic injection method," "vestibular-evoked myogenic potentials," "vestibular migraine," "magnetic resonance imaging," and "meniere's disease." The US has the largest number of publications and research institutions, many European countries have high-quality journals, and Japan has the highest number of scholars. The international opinion on Meniere's disease is relatively uniform. The stepped-therapy for MD is scientific and clear. Intratympanic injection of steroids and intratympanic injection of gentamicin are commonly used, but steroids are considered safer. Saccular dysfunction may be more common in patients with MD than in those with utricular dysfunctions. It is worth paying attention to study the relationship between MD and vestibular migraine through headache. Progress in magnetic resonance imaging technology is still required for the imaging diagnosis of MD.

Symptoms: Dizziness and Deafness

Symptoms: Dizziness and Deafness

Retrospective study of risk factors for tympanic membrane perforation in the early period after intratympanic steroid injection

ObjectiveIntratympanic steroid injection (ITSI) can be an effective treatment for sudden sensorineural hearing loss or Meniere's disease. Tympanic membrane (TM) perforation after ITSI is a major complication which needs additional treatment. The purpose of this study is to assess the factors associated with TM perforation after ITSI. MethodsWe obtained the clinical data of patients who underwent ITSI treatment at the Department of Otolaryngology JR Tokyo General Hospital from April 2013 to March 2021. The data included age, sex, treated side, number of injections, average interval between injections, TM anesthesia with Zentöl solution, which contains phenol, any history of diabetes and any concurrent use of oral or intravenous steroids. We evaluated the association between these variables and TM perforation after ITSI using the Student's t-test, the chi-squared test, univariate logistic regression analysis and multivariate logistic regression analysis. TM perforation was defined as a case in which perforation was observed at least once during outpatient visits. ResultsRecords of 205 ears in 190 patients were analyzed. The overall proportion of TM perforation in the early period after ITSI was 12.7% (26 out of 205 ears), which decreased to 9.3% (19 out of 205 ears) and 5.9% (12 out of 205 ears) at the 1- and 3-month follow-ups, respectively. The proportion of TM perforation in the early period after ITSI without TM anesthesia was 3.5% (5 ears out of 145 ears), which decreased to 1.4% (2 ears) or 0% at the 1- or 3- month follow-ups, respectively. The use of tympanic anesthetics which contain phenol was significantly associated with TM perforation in univariate logistic regression analysis (odds ratio: 15.08, 95% confidence interval: 5.34–42.56, p < 0.001) and in multivariate analysis (odds ratio: 20.76, 95% confidence interval: 6.31–68.3, p < 0.001). All TM perforation cases without TM anesthesia healed spontaneously or with paper tympanic closure treatment. TM perforation in 6 ears out of 21 ears with TM anesthesia did not heal during the follow-up. ConclusionThe overall proportion of TM perforations from the early period after ITSI was 12.7%, 9.3% at the 1-month post-ITSI outpatient follow-up, 5.9% at the 3-month post-ITSI outpatient follow-up. Tympanic anesthesia was significantly associated with TM perforation after ITSI, which indicated that TM anesthesia with solutions containing phenol is not recommended for ITSI.