Kathleen C. Horner

Rapidly fluctuating thresholds at the onset of experimentally-induced hydrops in the guinea pig

Pigmented guinea pigs were chronically implanted bilaterally with a platinum electrode on each round window. After recovery the endolymphatic sac was destroyed and the duct blocked on one side only; the other side was employed as a control. The round window response thresholds on both sides were recorded several times per week over a three month period. There were three main results. A sensitivity loss of up to 20 dB was observed for frequencies between 250 Hz and 6.4 kHz within two weeks post-op. At the end of three months the threshold elevation for these frequencies was as much as 50 dB. On the other hand the thresholds for frequencies between 8 and 16 kHz remained within 10 dB of their pre-operative value for at least two months. The thresholds fluctuated with a shift of as much as 25 dB within 24 h. The threshold elevation was associated with a decrease in the latency, at threshold, of the round window AP response which at frequencies between 250 Hz and 6.4 kHz was as short as that for 8 kHz. This observation suggested that it was the base, only, of the cochlea which responded. The present study has indicated that experimentally induced endolymphatic hydrops in the guinea pig mimics well the progressive and fluctuating hearing loss characteristic of Ménières disease.

Atrophy of middle and short stereocilia on outer hair cells of guinea pig cochleas with experimentally induced hydrops

Scanning electron microscopy was employed to investigate hair cell morphology at different stages in the development of experimentally induced hydrops in the guinea pig. A particular form of morpho-pathology, never before described, was identified as characteristic of hydropic cochleas. The pathology was characteristically identified as atrophy of the short and middle stereocilia on the outer hair cells while the inner hair cell stereocilia did not have such a pathology. The atrophy was restricted to the upper cochlear turns in remarkable correspondence with the low/middle frequency sensitivity loss and was detected only at the end of the period of fluctuating thresholds. These stereocilia perturbations appear therefore to be linked with the threshold fluctuations and represent the first evidence for a clear correlation between hair cell morphology and physiology in the experimental model of endolymphatic hydrops. Such a morphopathology might also be expected to occur in cochleas of Menières patients but may have been overlooked in the past because of the discrete nature of the pathology.

The effect of sex hormones on bone metabolism of the otic capsule – an overview

Bone resorption, which can occur after the menopause, has long been considered to due to the decrease of estrogen and so estrogen and estrogen/progestin treatment in women has been employed with the aim of slowing down the process. Other important factors have recently been considered, including follicle-stimulating hormone. The hormonal control of bone metabolism has taken on a new dimension since the description, within the last decade, of a major osteoclast inhibiting control system. The receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) produced by osteoblastic lineage cells, must bind with its receptor RANK, located on osteoclasts, in order to allow the maturation and activation of osteoclasts. The potential continuous bone loss is controlled by the decoy receptor osteoprotegerin (OPG) which competitively binds to RANKL and hence blocks the interaction of RANKL-RANK. Estrogen contributes to bone protection since it decreases the response of osteoclasts to RANKL and induces osteoclast apoptosis. But estrogen, alone and especially in synergy with progesterone, is a potent stimulator of prolactin release. Prolactin affects calcium metabolism and hyperprolactinemia associated with pregnancy, lactation, antipsychotic drug treatment, or aging is reflected in decreased bone mineral density. Long-term estrogen treatment in guinea pig results in hyperprolactinemia and has been shown to lead to hearing loss as well as bone dysmorphology of the otic capsule. Recent data show that prolactin decreases OPG and increases RANKL. OPG has been shown to be expressed at high levels in the cochlea and OPG knock-out mice have indeed abnormal remodeling of the otic capsule and resorption of the auditory ossicles. So estrogen-induced hyperprolactinemia could oppose estrogen protection by the knock-down of the OPG bone protection system. This might explain why oral contraception treatment and hormone replacement therapies, involving estrogen together with progestin, increases the risk of otosclerosis and vestibular disorders. Hyperprolactinemia associated with pregnancy and lactation might also underlie the association of increased risk of otosclerosis with multiple pregnancies.

Prolactinoma in Some Ménière's Patients — Is Stress Involved?

Dizziness is a common complaint in primary care clinics and can enter the diagnostic profile of different pathologies spanning from psychiatric problems to vestibular dysfunction. Episodes of vertigo in Ménières patients are often reported to be triggered by stress but no physiological data are available to account for the subjective link. The study involved 42 Ménières patients hospitalized for neurectomy of the vestibular nerve for relief of incapacitating vertigo. In addition 18 patients with neurinoma of the vestibular nerve and 12 patients with facial spasm, who underwent surgery, served as controls. A blood sample was taken on the day of surgery in order to determine the level of battery of different stress hormones. The most striking observation was the presence of hyperprolactinemia (above 20 μg/l) in 14 Ménières patients. The presence of prolactinoma was confirmed by MRI in six cases out of six investigated and the others have not yet been followed up in this retrospective study. These observations are clearly indicative for systematic determination of prolactin levels before opting for surgery in Ménières patients.

Independent Fluctuations of the Round-Window Summating Potential and Compound Action Potential following the Surgical Induction of Endolymphatic Hydrops in the Guinea Pig

The diagnosis of Menières disease is classically based on the triad of symptoms including fluctuating hearing loss, tinnitus and vertigo. Modifications to the electrocochleographic response have been searched as a possible help in the diagnosis. Various authors have reported a tendency for an increased ratio of the summating potential (SP) to action potential (AP) which is generally thought to be due to an enhanced SP. However, the large variability between patients has precluded any clear-cut conclusion. This dispersion of data might represent real individual differences or might be attributed to unavoidable technical variations, such as electrode placement and/or precise control of stimulus levels. As an attempt to answer this issue, we employed an animal model of experimental hydrops in which these difficulties can be overcome by chronic implantation of round-window electrodes and carefully controlling the stimulus level. In the present study, the SP and AP were monitored over several months for different frequencies and different intensities. In the early period of fluctuating thresholds at low and mid frequencies, AP amplitude varied in loose correspondence with the fluctuating audiogram. The SP amplitude also varied apparently not associated with AP or threshold changes and no consistent increase in SP was observed. At a later stage when all thresholds were elevated both SP and AP diminished. In normal ears increases in the stimulus intensity induce an augmentation of SP/AP. In hydropic ears, at the period of fluctuating thresholds, the SP/AP growth curve was at first similar to that of controls but later became very variable for different animals, but in general much larger than normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of Increased Endolymphatic Pressure to Hearing Loss in Experimental Hydrops

After the induction of experimental hydrops there follows a strict sequence of compound action potential (CAP) audiogram changes. Within days a low-frequency loss (below 8 kHz) is detected; within weeks a very high-frequency loss (above 8 kHz) develops; and finally within months the 8-kHz region is also affected. Following the application of excess pressure, presumably to the endolymphatic spaces, via a cannula placed in the endolymphatic duct, a sequence of CAP audiogram changes occurs that is not similar to that observed with hydrops. There is first a very high-frequency loss (above 4 kHz), then a very low-frequency loss (below 4 kHz), and finally the 4 kHz region is also affected and thresholds for all frequencies become even more raised. The data thus suggest that a slow accumulation of endolymph as induced by blockage of the endolymphatic duct does not produce the same disorder as a rapid onset of a high pressure applied at the base of the cochlea. In addition the data suggest that raised endolymphatic pressure is not likely to be significant in early stages of hydrops, but could contribute to the later high-frequency sensitivity losses.

Asymmetry of Evoked Rotatory Nystagmus in the Guinea Pig after Experimental Induction of Endolymphatic Hydrops

We have previously shown by chronic implantation of round window electrodes, that after the experimental induction of endolymphatic hydrops by surgical blockade of the endolymphatic canal, in the guinea pig, there is a low/mid-frequency fluctuant hearing loss, followed by a very high frequency loss and after a few months the audiogram is flat. This evolution reproduces exactly that observed in Menieres patients. The aim of this study was to investigate the evolution of one aspect of vestibular function in parallel with audiogram changes. The nystagmic responses in the dark were tested every month during the 4 months which followed hydrops induction. There was considerable variation in the number of evoked saccades for different control animals and even between different recordings for the same control animal. However, in general, the number of saccades to right and left rotation was symmetrical for control animals, whereas for hydropic animals there was a period, within the first 2 months post-operation, when there was a reduction of saccades to the left (operated side) with sometimes an increase to the right. This asymmetry which occurred in the period of fluctuant hearing losses did not however appear synchronized with audiogram fluctuations. The nystagmic responses tended to become symmetrical over the 4 months post-operation. Oral administration of glycerol to animals whose nystagmus was asymmetric brought the vestibular response towards symmetry in 50% of the cases. Although episodes of vertigo, as known in Menieres disease, were never observed in operated guinea pigs, these data indicate that they have some functional vestibular disturbance.

Atrophy of outer hair cell stereocilia and hearing loss in hydropic cochleae

We have earlier described selective atrophy of short and middle stereocilia on outer hair cells of the three upper cochlear turns in hydropic cochleae of guinea pigs. The present study describes sequential early stages of stereocilia degeneration leading to this specific atrophy. Comparison of the morpho-pathology with the ultimate CAP audiograms taken before sacrifice indicated a close association between the low frequency hearing loss and this atrophy of stereocilia. The atrophy appeared to be associated first with the short and then the middle stereocilia of the 2nd and 3rd rows of outer hair cells between 0.5 kHz and 2 kHz and with time included the 1st row of all outer hair cells of the upper cochlear turns down to the 8 kHz region.

Long-term Treatment with Chlorthalidone Reduces Experimental Hydrops But Does Not Prevent the Hearing Loss

Long-term treatment of guinea pigs with the diuretics chlorthalidone and acetazolamide, following the experimental obstruction of the endolymphatic duct, was assessed using chronically implanted round window cochlear electrodes. The diuretic chlorthalidone appeared to curb the progressive low-frequency sensitivity loss during the first 4 weeks following surgery, as compared with animals receiving the diuretic acetazolamide or no treatment. However, this apparent beneficial effect decreased after 4 weeks and was not apparent at 14 weeks post-induction. On the other hand, morphological control at the end of 14 weeks confirmed a marked reduction in hydrops in the chlorthalidone-treated animals. The data clearly demonstrate a dissociation between hydrops and the development of hearing loss and suggest that the augmenting endolymph volume is only one of several contributing factors to the deteriorating auditory function in experimental hydrops.

Distortion products in early stage experimental hydrops in the guinea pig

The swelling of the endolymphatic spaces in experimental hydrops is likely to induce mechanical changes all along the cochlea. The selective atrophy of short and middle stereocilia on the outer hair cell above the first cochlear turn is expected to alter micromechanics and transduction. Two tone stimuli were employed in the present study to investigate cochlear distortion products in hydropic ears. Despite a substantial low frequency sensitivity loss on the CAP audiogram, 2f1-f2 distortion products recorded in the RWCM and the CAP were similar in hydropic ears and normal control ears which reflect the probable common origin of these responses--the base of the cochlea where no threshold shifts can be detected. On the other hand this distortion product in the otoacoustic emissions was considerably reduced in hydropic cochleas when the primary tones lay within the pathological part of the audiogram. The reduction of CDT emissions cannot be accounted for by hair cell loss since at the early stage of hydrops described here there is only discrete hair cell loss which is restricted to the apex of the cochlea. On the other hand the reduction in the amplitude of the CDT might reflect disturbance in hair cell function and/or cochlear mechanics above the first cochlear turn.