Third Window Syndrome Volume II

P. Ashley Wackym ^1* Carey David Balaban ² Konstantina M Stankovic ³ Tetsuo Ikezono ⁴ Todd M. Mowery ¹

• ¹ Department of Head and Neck Surgery & Communication Sciences, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
• ² Department of Otolaryngology, Head and Neck Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ³ Department of Otolaryngology – Head and Neck Surgery, Stanford University School of Medicine, Palo Alto, United States
• ⁴ Department of Otolaryngology and Neuro-Otology, Saitama Medical University Hospital, Saitama, Japan

Nearly a century ago, Tullio described the physiologic outcomes of creating a third mobile window in the semicircular canals of pigeons (1,2). Since that time, many locations of third mobile windows have been described; however, the sound-induced dizziness and/or nystagmus has been memorialized by the eponym 'Tullio phenomenon.' Clinically, the best-known and most thoroughly characterized third mobile window is superior semicircular canal dehiscence. In 1998, Minor and coworkers first reported sound-and/or pressure-induced vertigo due to bone dehiscence of the superior semicircular canal, confirmed on CT scans (3). Minor later reported a conductive hearing loss, which was recognized as an inner ear conductive hearing loss (i.e. bone-conduction hyperacusis), as well as a reduced cervical vestibular myogenic potential (cVEMP) threshold in patients with superior semicircular canal dehiscence. While the clinical phenotype associated with the superior semicircular canal dehiscence is well-recognized; third window syndrome with the same clinical phenotype has been reported in patients without radiographic evidence of a frank superior semicircular canal dehiscence (4)(5)(6)(7)(8)(9). Such a CTnegative third window syndrome is associated with an inner ear conductive hearing loss and an abnormally reduced cVEMP threshold, among other objective findings typically found in patients with superior semicircular canal dehiscence (4)(5)(6)(7)(8)(9). The more general term of Third Window Syndrome has gained acceptance because the same spectrum of symptoms, signs on physical examination and audiological diagnostic findings are encountered with superior semicircular canal dehiscence, cochlea-facial nerve dehiscence, cochlea-internal carotid artery dehiscence, cochlea-internal auditory canal dehiscence, lateral semicircular canal-superior semicircular canal ampulla dehiscence, modiolus, "perilymph fistula," posterior semicircular canal dehiscence, posterior semicircular canal-endolymphatic sac dehiscence, posterior semicircular In this editorial, we present an overview of the 12 published studies included in this Research Topic, organized into the following categories: New Animal Model; Diagnostic Studies and New Diagnostic Tools; Sites of Dehiscence; Surgical Advances; and Surgical Outcomes. Wackym et al. have developed and reported a gerbil model of superior semicircular canal dehiscence, displaying reversible diagnostic findings that are characteristic of patients with the disorder, such as an inner ear conductive hearing loss and increased amplitude cervical positive vestibular evoked myogenic potentials. Using this animal model, Mowery et al. demonstrated reversible impairments in specific auditory and visual behavioral tasks assessing decisionmaking, suggesting a potential link between vestibular dysfunction and cognitive deficits. These animals with superior semicircular canal dehiscence demonstrate reversible deficits in a spatial two-alternative forced-choice task, in which they must choose between a left or right to receive a food reward. Together, these findings show how important proper vestibular function is to normal behaviors. Most recently, Hong et al. used the same gerbil superior semicircular canal dehiscence model to confirm that aberrant asymmetric vestibular output results in reversible balance impairments, similar to those observed in patients after superior semicircular canal dehiscence plugging surgery. Together, these findings show how important proper vestibular function is to normal behaviors, and the methodology used to establish the gerbil animal model can be employed in other species to systematically investigate the influence of vestibular function on peripheral ear and central cognitive processing. Third Window Syndrome has emerged as a significant clinical diagnosis, benefiting thousands of patients globally through its discovery and the development of effective treatments. Moreover, this syndrome serves as valuable pathologic phenomenon that enhances our understanding of the physiology of the vestibular end organs, and aids in the development and refinement of diagnostic tools that probe various aspects of the vestibular system. Kileny et al. studied the diagnostic utility of electrocochleography (EcochG) relative to the inner ear conductive hearing loss in 20 patients with confirmed superior semicircular canal dehiscence. Eleven patients had unilateral superior semicircular canal dehiscence, and nine patients had bilateral superior semicircular canal dehiscence demonstrated by high-resolution temporal bone CT scanning. There were twenty-nine ears with superior semicircular canal dehiscence and 11 normal ears included in their study. They found that all confirmed superior semicircular canal dehiscence ears presented with an abnormal EcochG summating potential to action potential (SP/AP) ratio value and that there was a statistically significant difference between normal and dehiscent ears. There was no statistically significant relationship between inner ear conductive hearing loss air-bone gap and SP/AP ratio in the ears diagnosed with superior semicircular canal dehiscence nor was there a significant difference between dehiscent and normal ears in terms of inner ear conductive hearing loss air-bone gap at three frequencies. The authors concluded that EcochG remains a valuable diagnostic tool for superior semicircular canal dehiscence. They also emphasized that the variability in the air-bone gap associated with inner ear conductive hearing loss should not drive the decision to include EcochG in the diagnostic test battery for patients suspected of having this condition.Ito et al. reported the case of a 27-year-old female who complained of hearing disturbance in her right ear and recurrent vertigo after sudden onset of hearing loss with vertigo. She had reduced vestibular function in the affected ear demonstrated by caloric testing and video head impulse testing. The innovative diagnostic testing reported used a contrast-enhanced MRI technique using hybrid of reversed positive image of endolymph signal and a negative image of perilymph signal which they interpreted as a collapsed endolymphatic space. After failed medical management and with persistent vestibular symptoms, an exploratory right tympanotomy was performed and both the round and oval windows were sealed with connective tissue. The patient's vestibular symptoms rapidly improved after surgery, and postoperative contrast-enhanced MRI showed improvement in the collapsed endolymphatic space. Although the caloric test revealed unilateral weakness, the VOR gain on the vHIT improved to normal on the right side. Thus, these findings indicated that recurrent symptoms caused by a perilymph fistula are associated with a collapsed endolymphatic space. They speculated that the collapsed endolymphatic space was due to a ruptured Reissner membrane. They further hypothesized that sealing the fistula resulted in normalization of the perilymph pressure by healing of the ruptured Reissner membrane. This case added to the existing literature on the occurrence of the "double-membrane break syndrome." Kubota et al. compared the diagnostic accuracy of endoscopic middle ear exploration to assaying the presence of perilymph specific cochlin-tomoprotein in the middle ear to diagnose idiopathic perilymphatic fistula. Perilymph fistula can be difficult to diagnose in patients who present with sudden sensorineural hearing loss and/or vestibular symptoms without any antecedent events. The authors studied five patients who were initially treated with intratympanic dexamethasone for sudden sensorineural hearing loss, at which time a preoperative cochlin-tomoprotein test was also performed. For patients who did not respond to the intratympanic corticosteroids, endoscopic perilymph fistula repair was performed to seal the oval and round windows using connective tissue and fibrin glue. The authors evaluated preoperative and intraoperative cochlin-tomoprotein values, intraoperative endoscopic surgical findings, and preoperative and postoperative changes in hearing levels and vestibular symptoms. Preoperative and intraoperative cochlin-tomoprotein values were positive and intermediate in three patients, positive and negative in one patient, and negative and positive in one patient. None of the patients had intraoperative endoscopic findings consistent with a fistula between the inner and middle ears or leakage of perilymph. Only two patients showed a slight postoperative recovery in hearing. Four patients reported experiencing disequilibrium preoperatively, and two of them experienced postoperative resolution of disequilibrium. The authors concluded that a positive cochlin-tomoprotein test can confirm perilymph fistula in patients without obvious intraoperative endoscopic findings. Ionescu et al. published an interesting series of complex superior semicircular canal dehiscence patients whose outcomes were not as successful as expected. After reviewing the radiological and clinical files, they speculated that the treatment failure in these patients may be due not only to surgical technique errors, as was discussed in one case, but also due to the simultaneous presence of other sites of dehiscence in the otic capsule that had not been diagnosed before each patient's superior semicircular canal dehiscence surgery. This prompted Ionescu et al. to conduct a retrospective analysis of high-resolution temporal bone CT scans from 157 patients (314 ears) over a five-year period, focusing on both symptomatic and asymptomatic Third Window Syndrome. They sought to determine the incidence of multiple dehiscence sites in this population. The results revealed that multiple suspected sites of otic capsule dehiscence in the ipsilateral ear were relatively common, occurring in 29 of 157 patients (18.47%). These findings were similar to those reported in 2019 by Wackym and coworkers in the original Research Topic focused on Third Window Syndrome. They identified 463 temporal bones of ears with Third Window Syndrome symptoms (57.7% [463/802]) with a single site of dehiscence (superior semicircular canal dehiscence, near-superior semicircular canal dehiscence, CT negative Third Window Syndrome, cochlea-facial nerve, cochlea-internal auditory canal, wide vestibular aqueduct, lateral semicircular canal, modiolus and posterior semicircular canal, superior semicircular canal dehiscence and superior petrosal sinus, superior semicircular canal dehiscence and subarcuate artery). After excluding temporal bones with CT negative findings for Third Window Syndrome, single site temporal bone dehiscence was identified in 366 out of 402 cases (91.0%). Superior semicircular canal dehiscence and near-superior semicircular canal dehiscence were the most commonly observed sites of dehiscence (59% [296/502]). The second most commonly observed category of radiologic findings in the Third Window Syndrome cohort was CT negative Third Window Syndrome (19.3% [97/502]). The third most commonly observed site of dehiscence was cochlea-facial nerve dehiscence (10.4% [52/502]). Regarding multiple sites of dehiscence, there were 38 instances (38/405 [9.38%]) of two site dehiscence (superior semicircular canal dehiscence and cochlea-facial nerve dehiscence, cochlea-facial nerve dehiscence and cochlea-internal auditory canal, cochlea-facial nerve dehiscence and wide vestibular aqueduct, superior semicircular canal dehiscence and cochlea-internal auditory canal, superior semicircular canal dehiscence and posterior semicircular canal-jugular bulb). The combination of superior semicircular canal dehiscence and cochlea-facial nerve dehiscence accounted for 6% (30/502). There was one instance of three sites (3/405 [0.24%]) of dehiscence (superior semicircular canal dehiscence and posterior semicircular canal and wide vestibular aqueduct). Wackym recommended careful assessment of the potential additional dehiscence sites prior to determining the surgical approach for managing superior semicircular canal dehiscence.In this Research Topic, Seo et al. reported a case of a microfissure near the round window niche that communicated between middle ear and the ampulla of the posterior semicircular canal. They reported the first case of a patient successfully treated with perilymph fistula repair surgery, presenting with ipsilateral hearing loss, tinnitus described as a flowing-water sound, and a floating sensation triggered by pressing the left tragus, which was caused by an inner ear microfissure. An exploratory tympanotomy was performed eight days after onset of his symptoms, revealing intraoperative findings of a microfissure and an accumulation of clear fluid in the floor of the round window niche. The site of leakage was sealed with connective tissue. One month after surgery, his hearing and disequilibrium had improved suggesting that the microfissure was responsible for his auditory and vestibular symptoms. Sawada et al. described a multilayer round window reinforcement technique in managing patients with superior semicircular canal dehiscence. They described making an intrameatal incision, with harvesting of loose areolar tissue which was compressed with a fascia press and subsequently cut into 3-5 mm pieces. Cartilage and perichondrium were then harvested from the tragus, thinned with a scalpel, and cut into approximately 2-3 mm round diameters. Within the middle ear, a CO2 laser was used to remove the mucosa surrounding the round window niche. A small piece of thinly sliced cartilage with perichondrium was then positioned to fit within the bony overhang of the niche space, facing the perichondrium side toward the round window so that the cartilage would not damage the round window membrane. Tiny fragments of cartilage, approximately 0.25 mm in size, were positioned around the initial cartilage to fill the gaps with the bone and stabilize the structure. Additionally, thinned connective tissue was applied to envelop the first cartilage and these additional pieces, extending over the exposed bone surrounding the niche so that it would adhere to the bony surface. Subsequent layers of additional sliced cartilage were placed on top to prevent migration. Fibrin glue was used to secure these materials in place.To illustrate the outcomes of this technique, Sawada et al. reported two cases of superior semicircular canal dehiscence managed with their round window reinforcement surgical technique that showed reduction of several symptoms of superior semicircular canal dehiscence, including autophony, bone-conduction sensitivity, pulsatile tinnitus, sound or pressure-induced vestibular symptoms, and aural fullness. They also reported marked improvement in their Dizziness Handicap Inventory, Vertigo Symptom Scale Short Form and Niigata Persistent Postural-Perceptual Dizziness Questionnaire scores after surgery.Altamami et al. developed a manual neuronavigation technique to more consistently identify the superior semicircular canal and the site of dehiscence in superior semicircular canal dehiscence. While a computer-assisted neuronavigation system is useful to precisely identify the location of a superior semicircular canal dehiscence, there are several limitations regarding the cost of purchasing these systems and the need to charge patients for their use during the surgery. Additional limitations of computer-assisted neuronavigation systems are that more surgical time is required to set up, calibrate and use during middle cranial fossa superior semicircular canal dehiscence plugging, which is exacerbated when the surgeon's experience is limited. The study reported by Altamami et al. demonstrated a simple manual neuronavigation technique that can help neurotologic surgeons identify the superior semicircular canal dehiscence accurately and efficiently. They demonstrated that the use of "line A" on the preoperative high-resolution temporal bone CT axial cut, which measures the distance from the superior semicircular canal dehiscence to the lateral cortical part of the supra-auricular squamous bone, provides a precise distance that can be measured during surgery. These findings were supplemented by two instructional videos that explained and demonstrated the technique. Matsuda et al. contributed a retrospective study of 22 cases treated with perilymph fistula repair surgery after failure of conservative medical management. The authors analyzed the characteristics of these cases and evaluated the efficacy of the perilymph fistula repair surgery in treating the vestibular and auditory symptoms. They found that cases with antecedent events had significantly shorter intervals before surgery. The postoperative recovery from vestibular symptoms following surgical repair was rapid, with 82% of cases demonstrating marked improvement within a week, even in chronic cases. Despite the acknowledged absence of a control group in their study, the postoperative improvements in vestibular symptoms and statistically significant reduction in Dizziness Handicap Inventory scores suggest that the observed outcomes were attributable to the surgical intervention. Further, timely surgery showed improvements in hearing, with some benefits also seen in late-stage surgeries. Using the perilymph-specific protein cochlin-tomoprotein as a diagnostic biomarker, they demonstrated that a perilymph fistula was present and responsible for the disequilibrium and related auditory disturbances in their patient cohort. They also introduced a new hypothesis that the chronic disequilibrium experienced by many of these patients is due to enhanced mobility of the utricle and not to the presence of endolymphatic hydrops.Benchetrit et al. sought to identify predictors of symptom persistence after surgical management of superior semicircular canal dehiscence. They conducted a retrospective study of 132 ears in 126 patients who underwent superior semicircular canal dehiscence plugging via the middle cranial fossa or transmastoid approach. The authors used a previously published standardized symptomatology questionnaire from their preoperative and postoperative visits. The questionnaire asked patients to identify if their most bothersome complaint is hearing-related or balance-related. Binary (yes/no) responses were recorded for the subjective experience of 11 auditory symptoms (hearing loss, aural fullness, pulsatile tinnitus, non-pulsatile tinnitus, autophony (hearing your voice too loudly), hyperacusis, hearing your voice echo, hearing your footsteps, hearing your eyeballs moving or hearing hair brushing or shaving sounds too loudly) and eight vestibular symptoms (general dizziness, sense of imbalance, Tullio phenomenon, straining causing dizziness, physical activity causing dizziness, blowing your nose/sneezing/coughing causing dizziness, oscillopsia and positional dizziness). Information regarding postoperative resolution of primary (most bothersome) symptom complaint was obtained from reviewing the electronic medical record and stratified to the categories of resolved, improved and persisted. The preoperative versus postoperative survey results, demographic and clinical characteristics, operative characteristics, audiometric data and cervical vestibular evoked myogenic potential (cVEMP) thresholds were compared via univariate χ 2 and multivariate binary logistic regression analyses between those patients reporting full postoperative resolution of symptoms and persistence of one or more symptoms. The authors found that of the 132 ears in 126 patients, 119 patients (90.2%) reported postoperative resolution (n = 82, 62.1%) or improvement (n = 37, 28.0%) of primary (most bothersome) symptoms, while 13 patients (9.8%) reported persistence of primary symptoms. The median (interquartile range) and range between surgery and questionnaire completion were 9 months (4-28), 1-124 months, respectively. Analyzing all symptoms (primary and nonprimary) 69 (52.3%) and 68 (51.1%) patients reported complete postoperative auditory and vestibular symptom resolution, respectively. They found that the most likely persistent symptoms included imbalance (33/65, 50.8%), positional dizziness (7/20, 35.0%) and oscillopsia (44/15, 26.7%). Factors associated with persistent auditory symptoms included history of seizures (0% vs. 7.6%, p = 0.023), auditory chief complaint (50.0% vs. 70.5%), higher PTA (mean 19.6 vs. 25.1 dB, p = 0.043) and higher cervical vestibular evoked myogenic potential (cVEMP) thresholds at 1000 Hz (mean 66.5 dB vs. 71.4 dB, p = 0.033). A migraine diagnosis (14.0% vs. 41.9%, p < 0.010), bilateral radiologic superior semicircular canal dehiscence (17.5% vs. 38.1%, p = 0.034) and revision cases (0.0% vs. 14.0%, p = 0.002) were associated with persistent vestibular symptoms. They also found that neither superior semicircular canal dehiscence size nor location were significantly associated with symptom persistence (p > 0.05). The authors concluded that surgical plugging of a superior semicircular canal dehiscence results in a meaningful reduction in the majority of auditory and vestibular symptoms; however, the persistence of certain, mostly non-primary, symptoms and the identification of potential associated factors including migraines, pure tone average thresholds, cVEMP thresholds, bilateral superior semicircular canal dehiscence, and patients representing revision cases underscore the need for individualized patient counseling and management strategies. In this Editorial, we highlight the 12 published studies included in this Research Topic and organized them in the following categories: New Animal Model; Diagnostic Studies and New Diagnostic Tools; Sites of Dehiscence; Surgical Advances; and Surgical Outcomes.Research on new diagnostic tools indicates that Third Window Syndrome can provide valuable insights into the mechanisms of the inner ear. There are three key symptoms and physical signs that are essential for identifying Third Window Syndrome, regardless of specific location of the dehiscence: (1) sound-induced dizziness; (2) hearing internal sounds; and (3) hearing or feeling low frequency tuning forks in an involved ear when applied to a patient's knee or elbow. The sound-induced auditory and vestibular activity is distinct from other balance disorders because the transient vestibular afferent activity is uncoupled from motion of the head or body in space (allocentric reference frame) or from motion of the environment around the head and body (egocentric reference frame). The sound-induced auditory and vestibular activity will also be uncorrelated with contextual visual, somesthetic and interoceptive sensory information and ongoing (or planned) motor activity. While the studies examining cognitive and spatial orientation in Third Window Syndrome shed light on important cognitive outcome measures for researching patients with vestibular impairments, neither their measures nor validated survey instruments for symptoms -such as the Dizziness Handicap Inventory -are specifically tailored to account for the distinctive perceptual incongruities present in Third Window Syndrome compared to other conditions. Although current tools may be useful for monitoring patient outcomes in the management of Third Window Syndrome, there is potential for improvement and refinement. The studies included in this Research Topic provided useful conceptual and state-of-the-art frameworks to better understand peripheral bases for the signs and symptoms of common forms of Third Window Syndrome. In addition, a series of basic research studies developing a new animal model of superior semicircular canal dehiscence creates the opportunity to study the fundamental neuroanatomic circuitry underlying the changes in cognitive dysfunction and other central nervous system phenomena that patients with Third Window Syndrome experience. These frameworks are essential for designing specific diagnostic tests and new, potentially therapeutic approaches. Finally, rare and newly identified sites of dehiscence creating a third mobile window were presented and surgical advances to manage various sites resulting in Third Window Syndrome were reported. Together, these 12 studies provide a comprehensive overview of our current knowledge, as well as gaps that remain in understanding, diagnosing and managing of patients with Third Window Syndrome.