Recommendations for cancer prevention trials using potentially ototoxic test agents.

PURPOSE: Preventive oncology applies pharmacologic agents to reverse, retard, or halt progression of neoplastic cells to invasive malignancy, a process that may require administration of agents over long periods of time. Although ototoxicity may be a tolerable side effect of anticancer or antimicrobial therapy, even modest ototoxicity may not be acceptable in agents developed for preventive oncology that are routinely administered to subjects who neither are, nor necessarily will become, clinically ill. MATERIALS AND METHODS: Age-related shifts in hearing may occur over the course of longterm or open-ended therapy; consequently, age-adjusted norms enable researchers to better distinguish hearing loss caused by drugs from that caused by aging. Norms for hearing sensitivity are derived from the Baltimore Longitudinal Study of Aging and are the basis for the proposed audiologic monitoring recommendations. RESULTS: Audiologic monitoring recommendations are presented that standardize patient selection, adverse event reporting, posttreatment follow-up, and audiologic testing for potentially ototoxic investigational agents. CONCLUSION: These recommendations are applicable to trials of investigational agents as well as various classes of drugs used in routine clinical care.

No evidence of hearing loss in humans due to transcranial magnetic stimulation.

Prompted by the description of hearing loss in rabbits exposed to the acoustic artifact of magnetic stimulation, we compared the results of audiologic studies before and after exposure to transcranial magnetic stimulation in humans. We found no evidence of temporary or permanent threshold shifts in any of the subjects, even in those exposed to transcranial magnetic stimulation repeatedly for several years. Risk of hearing loss from the acoustic artifact of magnetic stimulation, as evaluated by audiograms, tympanograms, acoustic reflexes, and auditory evoked potentials, seems to be small in humans.

Auditory dysfunction in Stickler syndrome.

OBJECTIVES: To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders. DESIGN: Multifamily study. SETTING: Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md. SUBJECTS: Forty-six affected individuals from 29 different families segregating Stickler syndrome. INTERVENTIONS: Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants. RESULTS: The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals. CONCLUSIONS: The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders.

No specific effects of caloric stimulation on the visual-imagery processes of normal subjects.

Recent research indicates that neglect can be temporarily, but only partially, ameliorated by activating the contralateral hemisphere via caloric stimulation and other techniques. In this study, we evaluated whether caloric stimulation could be used to manipulate visual-imagery processes in normal subjects. 11 normal subjects participated in a quantitative visual-imagery task while undergoing caloric stimulation. Neither side of report nor ear of caloric stimulation affected performance. Possible reasons for this negative result are reviewed.

Dosimetry measurements using a probe tube microphone in the ear canal.

Federal and international standards recommended use of microphone placement either on or in the vicinity of the shoulder for dosimetry to minimize deviations from the undisturbed sound field. Probe microphone measurements from the ear canal were compared to shoulder and chest measures in order to investigate the validity of current dosimetry methodologies. Six subjects were monitored in an industrial setting. As expected, ear-canal levels exceeded other measures for all subjects. Shoulder and chest measures showed very low intersubject variability whereas ear-canal measures resulted in large intersubject variability. The ear-canal methodology has the potential to identify individuals whose external ear gain exceed the mean, putting them at increased risk of noise-induced permanent threshold shift (NIPTS). It is proposed that overall external ear pressure gain be used as an index to adjust exposure levels when predicting NIPTS using ISO 1999. A normative database of external ear pressure gain was constructed from 30 ears for this purpose.

The effect of probe tube reference placement on sound pressure level variability.

This study examined the effect of external microphone reference placement on peak sound pressure level (pSPL) and measurement variability. Nine normal subjects were seated in a double-walled sound suite, 1 m and 0 degrees azimuth from a wall-mounted speaker. Digitized Gaussian noise was presented at 80 dB pSPL with a 500 msec duration and was measured through a probe tube microphone assembly. Replicated measurements were made at five locations external to the pinna. They were: anterior-superior and posterior-superior positions simulating hearing aid microphone placement (locations 1 and 2) and 2, 4, and 6 cm lateral to the lateral edge of the pinna (locations 3, 4, and 5). Means, standard deviations, and ranges were compared, and statistical analyses were performed. The highest pSPL values were recorded lateral to the pinna, and the lowest values were obtained at the simulated hearing aid positions. ANOVAs indicated a main effect for pSPL, and post hoc testing demonstrated a significant difference between the posterior-superior and 2 cm lateral to the pinna positions. Variability was largest at the posterior-superior and 6 cm positions, and lowest 2 cm from the pinna. From this study, we concluded that pSPL and variability are both important criteria for selecting an optimal reference microphone site and both can affect the accuracy of ear canal measurements. A reference site 2 cm from the pinna eliminates attenuation of the signal and is the least variable site.

Safety of rapid-rate transcranial magnetic stimulation in normal volunteers.

In 9 normal volunteers, we studied the safety of rapid-rate transcranial magnetic stimulation (rTMS) applied to different scalp positions at various frequencies and intensities. Pure tone threshold audiometry showed temporary threshold shifts in 3 subjects. In the subject stimulated at the highest intensity, rTMS induced a focal, secondarily generalized seizure despite the absence of definite risk factors for seizures. Rapid-rate TMS did not result in any important changes in the neurological examination findings, cognitive performance, electroencephalogram, electrocardiogram, and hormone levels (prolactin, adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone). In 10 additional subjects, the electromyographic activity in several contralateral muscles showed that trains of rTMS applied to the motor cortex induced a spread of cortical excitability. The spread of excitability depended on the intensity and frequency of the stimuli and probably constituted an early epileptogenic effect of rTMS. Guidelines for preventing the undesirable side effects of rTMS are offered.