Anthony A. Mikulec

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.

Volatile anesthetics depress glutamate transmission via presynaptic actions

Background Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate‐mediated transmission in the mammalian central nervous system. Methods Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate‐mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium‐dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms. Results Isoflurane depressed EPSP amplitudes over a concentration range of 0.35–2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired‐pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration‐dependent manner (0.3–2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 micro Meter bicuculline, indicating that enhanced gamma‐aminobutyric acid‐mediated inhibition was not involved. The anesthetic‐induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione depressed EPSP amplitudes with no change in facilitation. Conclusions Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate‐mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic‐induced depression of excitatory transmission. This anesthetic‐induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.

Head and Neck Cancer in Cardiothoracic Transplant Recipients

Introduction There is an increased incidence of cancer in patients after organ transplantation. We reviewed a large series of cardiothoracic transplant recipients to determine the incidence and natural history of head and neck malignancy.

Entry of substances into perilymph through the bone of the otic capsule after intratympanic applications in guinea pigs: implications for local drug delivery in humans.

Hypothesis: Drugs applied to the middle ear enter perilymph through the bony otic capsule. Background: Drugs applied intratympanically in humans are thought to enter the cochlea primarily through the round window membrane (RWM). Local drug treatments of the ear are commonly evaluated in rodent models. The otic capsule is much thinner at the cochlear apex in rodents than in humans. We therefore investigated whether drugs applied to the middle ear could enter perilymph through the otic capsule as well as through the RWM. Methods: The distribution of gentamicin and the marker trimethylphenylammonium (TMPA) along the guinea pig cochlea was assessed with sequential apical perilymph sampling after 2 delivery paradigms that included 1) completely filling the tympanic bulla with solution and 2) applying the solution to the RWM only. In addition, TMPA entry into perilymph of the third turn was measured with ion-selective electrodes after the bulla was filled with TMPA solution. Results: In application protocols that allowed drug to contact the otic capsule (by completely filling the bulla), markedly higher drug concentrations were found in the apical, low-frequency regions of the cochlea compared with drug applications to the RWM only. Conclusion: Gentamicin and TMPA can enter perilymph of guinea pigs through the RWM and simultaneously through the bony otic capsule. Drug distribution along the cochlea after intratympanic applications will therefore be dramatically different in rodents and humans. Results obtained from intratympanic drug treatments of animals, in which the bulla is filled with solution and contacts the bony capsule of the cochlea, do not provide a good model for the situation in humans.

Riluzole anesthesia : Use-dependent block of presynaptic glutamate fibers

Background Riluzole (RP 54274) is an experimental benzothiazole with anesthetic properties, but little is known about its synaptic or cellular actions. Methods The authors investigated riluzole effects on synaptic response of CA 1 pyramidal neurons in rat hippocampal brain slices. Electrophysiologic recordings of population spikes (PS), excitatory postsynaptic potentials (EPSP), and fiber volleys were studied. Paired pulse stimulation (120 ms interpulse interval) was used to measure effects on gamma-amino butyric acid (GABA)-mediated synaptic inhibition, and stimulus trains (33 Hz) were used to test for use-dependent effects. Results Synaptically evoked PS discharge was blocked in a concentration-dependent manner by riluzole (2.0-20 micro Meter), similar to effects produced by other anesthetics. Paired pulse inhibition was not altered by riluzole. In contrast, 20 micro Meter thiopental produced a marked increase in paired pulse inhibition. Riluzole (5.0 micro Meter) produced a 46.6 plus/minus 19.8% depression of glutamate-mediated EPSPs, which could account for most of the depression of PS discharge (54.2 plus/minus 12.6%) produced by this concentration. Riluzole produced a 36 plus/minus 17% depression of fiver volley amplitudes, which, based on input/output analysis, could completely account for the depression of EPSPs. The depression of fiber volley amplitudes showed a marked use-dependence; the second and subsequent action potentials in a train were progressively depressed by riluzole to a greater extent than the first action potential. Conclusions Riluzole produced a potent block of excitatory synaptic transmission via depression of presynaptic conduction in glutamatergic nerve fibers. The use-dependent depression observed resembled that produced by some local anesthetics on nerve conduction and sodium channels. The presynaptic action, together with a lack of effect on gamma-amino butyric acid-mediated inhibition, provides a unique mechanism of action for a general anesthestic.

Permeability of the round window membrane is influenced by the composition of applied drug solutions and by common surgical procedures.

Introduction: Intratympanic drug delivery has become widely used in the clinic, but little is known regarding how clinically used drug preparations affect round window membrane (RWM) permeability or how much drug is actually delivered to the cochlea. This study evaluated the effect of clinically relevant carrier solutions and of suction near the RWM on the permeability properties of the RWM. Methods: RWM permeability was assessed by perfusion of the marker trimethylphenylammonium into the round window niche while monitoring entry into perilymph using trimethylphenylammonium-selective electrodes sealed into scala tympani. Results: High-osmolarity solution increased RWM permeability by a factor of 2 to 3, benzyl alcohol (a preservative used in some drug formulations) increased permeability by a factor of 3 to 5, and suctioning near the RWM increased permeability by a factor of 10 to 15. Conclusion: Variations in available drug formulations can potentially alter RWM permeability properties and affect the amount of drug delivered to the inner ear. Drug solution osmolarity, benzyl alcohol content, and possible drying of the RWM during suctioning the middle ear can all have a substantial influence of the perilymph levels of drug achieved.

Operative Management of a Posterior Semicircular Canal Dehiscence

Objective: The objective of this study was to describe the operative management of posterior canal dehiscence.

Halothane depresses action potential conduction in hippocampal axons

General anesthetics are thought to depress the central nervous system (CNS) by acting at synapses; however, only a few studies have compared effects on axonal conduction with effects on synaptic responses using mammalian CNS preparations. The present study used glutamate receptor antagonists (CNQX/APV) or low calcium to block synaptic transmission, allowing Schaffer-collateral axon fiber volleys to be recorded from rat hippocampal brain slices. Since fiber volleys are compound action potentials, they provide a measure of axonal conduction in Schaffer-collateral fibers. Clinical concentrations of the inhalational anesthetic, halothane (1 rat MAC, 1.2 vol.%), produced an 18 +/- 2.3% depression of fiber volley amplitudes (mean +/- S.D.; p < 0.001 ANOVA, n = 10). Depression of action potential conduction accounted for approximately 30% of the overall depression of synaptic transmission produced by halothane at this concentration. Halothane-induced fiber volley depression occurred with little change in conduction velocity, similar to the effect seen with decreased stimulus intensity, but significantly different from the decreased velocity produced by tetrodotoxin (100 nM, p < 0.005). The results indicate that halothane can depress axonal conduction at clinically relevant concentrations and that this depression could contribute to the CNS depression that is associated with anesthesia.

Rapid clearance of methylprednisolone after intratympanic application in humans. Comment on: Bird PA, Begg EJ, Zhang M, et al. Intratympanic versus intravenous delivery of methylprednisolone to cochlear perilymph. Otol Neurotol 2007;28:1124-30.

The study by Bird and co-authors (1) is extremely important to the field of drug delivery to the inner ear as it provides the first measurements of human perilymph levels of a glucocorticoid (methylprednisolone, MP) following local intratympanic application. Perilymph samples were taken at various times (20 min to 3 hrs) after application and the measurements tabulated. However, because of the variability they observed, the authors chose to pool their data which were presented as a simple scatterplot. We re-analyzed the raw data taking into account the timing of the samples, from which we have been able to derive important pharmacokinetic parameters for MP entry into the inner ear. The symbols in Figure 1 show Bird et al.’s data replotted based on the sample timing information. It is apparent that samples taken at 1 hour show consistently higher levels than samples taken at longer times (2 hrs, 3 hrs) that are uniformly low. We have used computer simulation methods (2) to calculate expected sample concentration time courses as kinetic parameters were varied. The most important variable affecting the time course is the rate of drug clearance from the system. The rate of clearance was varied while calculating the sum of squares of deviations between calculated sample values and those obtained experimentally. The lowest sum of squares, indicating best fit, was found with a clearance half-time of 27 min. This estimated rate of clearance for MP was somewhat faster than that calculated for prednisolone based on prior experiments in guinea pigs, which occurred with a half-time of 130 min (2;3).

Association between osteoporosis and otosclerosis in women.

Similarities between osteoporosis and otosclerosis have been noted, including a similar association with the COL1A1 gene. Herein, the authors explore the possible clinical relationship between these two common disorders of bone. In this retrospective study, the medical charts of 100 women aged 50 through 75 years who had undergone stapedectomy for otosclerosis were reviewed and the prevalence of osteoporosis in these women was noted. Similarly, the prevalence of osteoporosis was determined in a control group of 100 women aged 50 to 75 years with presbycusis. Fifteen of 100 women with otosclerosis had a concomitant diagnosis of osteoporosis as compared with four of 100 women with presbycusis, yielding a significant clinical association (p = 0.007) between otosclerosis and osteoporosis. This study suggests an association between otosclerosis and osteoporosis, providing impetus and justification for future prospective clinical studies and related research.