Saumil N. Merchant

Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops?

Background: The association of Ménières syndrome with endolymphatic hydrops has led to the formation of a central hypothesis: many possible etiologic factors lead to hydrops, and hydrops in turn generates the symptoms. However, this hypothesis of hydrops as being the final common pathway has not been proven conclusively. Specific Aim: To examine human temporal bones with respect to the role of hydrops in causing symptoms in Ménières syndrome. If the central hypothesis were true, every case of Ménières syndrome should have hydrops and every case of hydrops should show the typical symptoms. Methods: Review of archival temporal bone cases with a clinical diagnosis of Ménières syndrome (28 cases) or a histopathologic diagnosis of hydrops (79 cases). Results: All 28 cases with classical symptoms of Ménières syndrome showed hydrops in at least one ear. However, the reverse was not true. There were 9 cases with idiopathic hydrops and 10 cases with secondary hydrops, but the patients did not exhibit the classic symptoms of Ménières syndrome. A review of the literature revealed cases with asymptomatic hydrops (similar to the current study), as well as cases where symptoms of Ménières syndrome existed during life but no hydrops was observed on histology. We also review recent experimental data where obstruction of the endolymphatic duct in guinea pigs resulted in cytochemical abnormalities within fibrocytes of the spiral ligament before development of hydrops. This result is consistent with the hypothesis that hydrops resulted from disordered fluid homeostasis caused by disruption of regulatory elements within the spiral ligament. Conclusion: Endolymphatic hydrops should be considered as a histologic marker for Ménières syndrome rather than being directly responsible for its symptoms.

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Superior semicircular canal dehiscence presenting as conductive hearing loss without vertigo.

Objective: The objective of this study was to describe superior semicircular canal dehiscence (SSCD) presenting as otherwise unexplained conductive hearing loss without vestibular symptoms. Study Design: Retrospective. Setting: Tertiary referral center. Patients: The study comprised 8 patients (10 ears), 5 males and 5 females aged 27 to 59 years. All 10 ears had SSCD on high-resolution computed tomography scan of the temporal bone. Diagnostic Tests and Results: All 10 ears had significant conductive hearing loss. The air–bone gaps were largest in the lower frequencies at 250, 500, and 1000 Hz; the mean gaps for these 3 frequencies for the 10 ears were 49, 37, and 35 dB, respectively. Bone-conduction thresholds below 2000 Hz were negative (−5 dB to −15 dB) at one or more frequencies in 8 of the 10 ears. There were no middle ear abnormalities to explain the air–bone gaps in these 10 ears. Computed tomography scan and laboratory testing indicated lack of middle ear pathology; acoustic reflexes were present, vestibular evoked myogenic potentials (VEMPs) were present with abnormally low thresholds, and umbo velocity measured by laser Doppler vibrometry was above mean normal. Middle ear exploration was negative in six ears; of these six, stapedectomy had been performed in three ears and ossiculoplasty in two ears, but the air–bone gap was unchanged postoperatively. The data are consistent with the hypothesis that the SSCD introduced a third mobile window into the inner ear, which in turn produced the conductive hearing loss by 1) shunting air-conducted sound away from the cochlea, thus elevating air-conduction thresholds; and 2) increasing the difference in impedance between the oval and round windows, thus improving thresholds for bone-conducted sound. Conclusion: SSCD can present with a conductive hearing loss that mimics otosclerosis and could explain some cases of persistent conductive hearing loss after uneventful stapedectomy. Audiometric testing with attention to absolute bone-conduction thresholds, acoustic reflex testing, VEMP testing, laser vibrometry of the umbo, and computed tomograph scanning can help to identify patients with SSCD presenting with conductive hearing loss without vertigo.

Clinical, experimental, and theoretical investigations of the effect of superior semicircular canal dehiscence on hearing mechanisms.

Hypothesis: A superior semicircular canal dehiscence affects hearing by introducing a third window into the inner ear that 1) lowers cochlear input impedance, 2) shunts air-conducted sound away from the cochlea resulting in conductive hearing loss, and 3) improves bone-conduction thresholds by increasing the difference in impedance between the vestibule and the round window. Background: Superior semicircular canal dehiscence has been linked to a “conductive” hearing loss characterized by a decrease in the sensitivity to air-conducted sound and hypersensitivity to bone-conducted sound. Methods: Four investigations were performed: 1) laser-Doppler vibrometer measurements of sound-induced umbo velocity in patients with computed tomographic scan–confirmed superior semicircular canal dehiscence; 2) laser-Doppler vibrometry of sound-induced motions of the vestibular lymph (either perilymph or endolymph) exposed in a chinchilla model of superior semicircular canal dehiscence; 3) studies in chinchillas of the effect of superior semicircular canal dehiscence on the cochlea’s sensitivity to bone-conducted sounds; and 4) anatomically based theoretical analyses of sound flow through the human cochlea and semicircular canals. Results: The low-frequency umbo velocity in superior semicircular canal dehiscence patients without previous middle ear surgery ranged from normal through high normal. This tendency toward hypermobility suggests a decrease in cochlear impedance. Measurements of sound-induced velocity of the lymph within a superior semicircular canal dehiscence in chinchillas demonstrated sound flow through the dehiscence. Measurements of the cochlear potential demonstrated a superior semicircular canal dehiscence-induced increase in response to bone-conducted sound in eight of nine chinchillas. An anatomically based model of the human ear predicts changes in auditory sensitivity similar to audiometric changes in superior semicircular canal dehiscence. Conclusion: The results suggest that superior semicircular canal dehiscence can affect hearing function by introducing a third window into the inner ear.

Pathology and pathophysiology of idiopathic sudden sensorineural hearing loss.

Background: The cause and pathogenesis of idiopathic sudden sensorineural hearing loss remain unknown. Proposed theories include vascular occlusion, membrane breaks, and viral cochleitis. Aims: To describe the temporal bone histopathology in 17 ears (aged 45-94 yr) with idiopathic sudden sensorineural hearing loss in our temporal bone collection and to discuss the implications of the histopathologic findings with respect to the pathophysiology of idiopathic sudden sensorineural hearing loss. Methods: Standard light microscopy using hematoxylin and eosin-stained sections was used to assess the otologic abnormalities. Results: Hearing had recovered in two ears and no histologic correlates were found for the hearing loss in both ears. In the remaining 15 ears, the predominant abnormalities were as follows: 1) loss of hair cells and supporting cells of the organ of Corti (with or without atrophy of the tectorial membrane, stria vascularis, spiral limbus, and cochlear neurons) (13 ears); 2) loss of the tectorial membrane, supporting cells, and stria vascularis (1 ear); and 3) loss of cochlear neurons only (1 ear). Evidence of a possible vascular cause for the idiopathic sudden sensorineural hearing loss was observed in only one ear. No membrane breaks were observed in any ear. Only 1 of the 17 temporal bones was acquired acutely during idiopathic sudden sensorineural hearing loss, and this ear did not demonstrate any leukocytic invasion, hypervascularity, or hemorrhage within the labyrinth, as might be expected with a viral cochleitis. Discussion: The temporal bone findings do not support the concept of membrane breaks, perilymphatic fistulae, or vascular occlusion as common causes for idiopathic sudden sensorineural hearing loss. The finding in our one case acquired acutely during idiopathic sudden sensorineural hearing loss as well as other clinical and experimental observations do not strongly support the theory of viral cochleitis. Conclusion: We put forth the hypothesis that idiopathic sudden sensorineural hearing loss may be the result of pathologic activation of cellular stress pathways involving nuclear factor-κB within the cochlea.

Meniere's Syndrome and Endolymphatic Hydrops: Double-Blind Temporal Bone Study

A systematic double-blind assessment of case histories and histopathologic findings in temporal bones in the collection at the Massachusetts Eye and Ear Infirmary was performed to test the hypothesis that clinical Menieres syndrome is associated with endolymphatic hydrops demonstrated histopathologically at death. Thirteen of 13 cases of clinical Menieres syndrome were found to have endolymphatic hydrops not attributable to other causes. However, some patients with idiopathic endolymphatic hydrops did not exhibit clinical Menieres syndrome as revealed in their medical records. These results challenge the dogma that endolymphatic hydrops per se generates the symptoms of Menieres syndrome.

Acoustic input impedance of the stapes and cochlea in human temporal bones

The acoustic input impedance of the stapes and cochlea ZSC represents the mechanical load driven by the tympanic membrane, malleus and incus. ZSC was calculated from broad-band measurements (20 Hz to 11 kHz) of stapes displacement made with an optical motion sensor and of sound pressure at the stapes head in a human temporal-bone preparation. Measurements were made in 12 fresh temporal bones with the round window insulated from the sound stimulus. Below 1 kHz, the magnitude of ZSC was approximately inversely proportional to frequency, and ZSC angle was between 0.10 and -0.20 periods. This behavior is consistent with a mixed stiffness and resistance. Between 1 and 4 kHz, ZSC was resistance-dominated with a magnitude between 40 and 100 mks acoustic G omega that was roughly independent of frequency, and its angle was between -0.12 and 0 periods. Between 4 and 7 kHz, the magnitude of ZSC was either constant or increased with frequency while ZSC angle was near 0. Between 7 and 8 kHz, both ZSC magnitude and angle decreased sharply with frequency, and both increased somewhat at higher frequencies. The input impedance of the cochlea ZC was estimated in one ear from ZSC measurements made before and after draining the inner ear fluids. ZC was stiffness-dominated below 100 HZ, and resistance-dominated from 100 Hz to 5 kHz. The frequency-dependent magnitude of ZSC in our bones is similar to those reported by other investigators in cadaver temporal bones (Nakamura et al., 1992; Kurokawa and Goode, 1995). Our ZSC measurements are qualitatively similar to theoretical predictions (Zwislocki, 1962; Kringlebotn, 1988), but are a factor of 3 greater in magnitude, implying that ZSC may be more resistive and stiffer than previously thought. We found inter-ear variations of a factor of 4 (12 dB), which may explain some of the clinically observed variations in size of the air bone gap in individuals with middle ear lesions or after middle-ear reconstructive surgery.

Vestibular evoked myogenic potentials (VEMP) can detect asymptomatic saccular hydrops.

Objective: The objective of this study was to explore the useful of vestibular evoked myogenic potential (VEMP) testing for detecting endolymphatic hydrops, especially in the second ear of patients with unilateral Ménière disease (MD).

Cadaver middle ears as models for living ears: comparisons of middle ear input immittance.

In vitro measurements of the middle ear input immittance in temporal bones extracted from human cadavers were directly compared with similar in vivo measurements from clinically normal subjects. The results of this comparison indicate that most otoscopically normal unfixed cadaver ears have middle ear input immittances that are indistinguishable from those of live subjects in the 0.1- to 2-kHz range — As long as they have been kept from drying and the static pressures on either side of the tympanic membrane are equal. The effects of the middle ear muscles on the measured input immittance are generally small and the cadaver ears can be maintained in the frozen state for several months with little change. Tympanometry appears to be a reliable indicator of normal middle ear immittance. Cadaver middle ears are useful models of human middle ear function.

Sudden Deafness: Is It Viral?

A number of theories have been proposed to explain the etiopathogenesis of idiopathic sudden sensorineural hearing loss (ISSHL), including viral infection, vascular occlusion, breaks of labyrinthine membranes, immune-mediated mechanisms and abnormal cellular stress responses within the cochlea. In the present paper, we provide a critical review of the viral hypothesis of ISSHL. The evidence reviewed includes published reports of epidemiological and serological studies, clinical observations and results of antiviral therapy, morphological and histopathological studies, as well as results of animal experiments. The published evidence does not satisfy the majority of the Henle-Koch postulates for viral causation of an infectious disease. Possible explanations as to why these postulates remain unfulfilled are reviewed, and future studies that may provide more insight are described. We also discuss other mechanisms that have been postulated to explain ISSHL. Our review indicates that vascular occlusion, labyrinthine membrane breaks and immune-mediated mechanisms are unlikely to be common causes of ISSHL. Finally, we review our recently proposed theory that abnormal cellular stress responses within the cochlea may be responsible for ISSHL.