A. CASE STUDY OF SALICYLATE INTOXICAE‘ION AND ITS EFFECT ON THE FUNCTEON 0? THE AUDITORY SYSTEM THESE; FOR "fl-{E DEGREE OF M. A. MECHEGAN STATE UNIVERSITY DIANE MAME GIRAUD! I976 ”-15.25% TTTTTTT TTTT TTTTTTT TTTTTTTTTT 3 1293 10736 653 h. Tam 1- 2.1! This thesis has been accepted by Michigan .State University in partial fulfillment of the requirements for the degree of Master of Arts, Department of Audiology and Speech Sciences, 1976. Steven C. White, Ph.D. (Director of thesis) Y. Pal Kapur, M.D. Linda L. Smith, Ph.D. ABSTRACT A CASE STUDY OF SALICYLATE INTOXICATIOE AND ITS EFFECT ON THE FUNCTION OF THE AUDITORY MECHANISM BY Diane M. Giraudi Aspirin is a commonly used non—prescription drug. It can, with large doses, induce transient hearing loss, tinnitus, and vertigo. This study examined the reaction of the auditory system to high levels of aspirin, i.e., salicylate, in a 39 year—old female patient whose auditory history was otherwise unremarkable. Peripheral and central auditory tests examined the re- action of the auditory system to salicylate intoxication. The test battery consisted of pure tone audiometry, speech audio— metry, tone decay testing, the Short Increment Sensitivity Index (SISI), impedance audiometry, otoadmittance audiometry, brief tone audiometry, the Staggered Spondaic Word test (Katz, Basil, and Smith, 1963), dichotic listening task, filtered speech, time compressed speech, and pitch match tasks. The patient's absolute hearing thresholds were found to be at the lower limits of the normal range with middle ear mobility and pressure within normal limits. The acoustic fl: J’g/ "1' v (:1? Diane M. Giraudi reflex was present bilaterally. Results of the Short Increment Sensitivity Index at high and low sensation levels demonstrated a normally funCtioning peripheral auditory system. The only direct indicator of cochlear pathology were the results of brief tone audiometry. However, this may be true because the other tests of cochlear disorder will, at times, fail to detect a Subclinical or slight cochlear lesion. The results of the pitch match tasks were at the upper limits of the conductive hearing loss category (Graham and Newby, 1962; Nodar and Graham, 1965). Central auditory testing consisted of time compressed monosyllables of the Northwestern University Auditory Test Number Six, low pass filtered speech, Staggered Spondaic Words, and dichotic consonant—vowels. Temporal lobe lesion due to salicylate intoxication was not indicated by these tests. Performance on the time compressed speech task did not markedly decrease across the levels O %, 30 %.and 60 % time compression. Filtered speech results were comparable to the normative data established by this study. The Staggered Spondaic Word test results demonstrated less than 1 % error. Simultaneously presented dichotic syllables did not indicate cerebral dominance. The findings of this case study appear to demonstrate a cochlear site of lesion since the integration function for Diane M. Giraudi acoustic energy was less than that seen in individuals with- out cochlear disorder. Tests examining retrocochlear function did not Show abnormal adaptation or increased sensitivity to small changes in intensity levels. Auditory functionat the cortical level was not impaired due to salicylate intoxica~ tion. A CASE STUDY OF SALICYLATE INTOXICATION AND ITS EFFECT ON THE FUNCTION OF THE AUDITORY MECHANISM BY Diane M. Giraudi A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF ARTS Department of Audiology and Speech Sciences 1976 ficr/ é; ACKNOWLEDGEMENTS I wish first to thank the members of my committee, Steven C. White, Ph.D., Linda L. Smith, Ph.D., and Y. Pal Kapur, M.D. for their guidance and assistance with my theSis. Most especially, I wish to thank Dr. White, I my thesis director, for standing by me throughout the ups and downs of this study. And my subject—~her enthusiasm and cooperation will long be remembered. To my parents for their encouragement and emotional support during my graduate studies, and in particular my thesis, thank you. To my friends Bonnie, Gail, Elaine, and Diane I thank you for listening and understanding. To Darry, Dan, and Steve, "by the same token," and "at any rate" thank you for teaching me and challenging me. And, to Gene, who asked the now famous question, "Has anyone ever done a pitch match with salicylates?”. You gave the push that got me into this and—~I learned. Thank you. TABLE OF CONTENTS LIST OF TABLES ........................... ...............page 1 LIST OF FIGURES ....... . ...... . ................... . ..... page ii CHAPTER I. INTRODUCTION........ ............ ............page 1 Early Research... ...... . ..... ....... ..... ...page 2 Recent Investigations.. ...... ........ ....... page 4 II. III. Characteristics of Salicylate Induced Hearing Loss...... ....... ...... ..... ...page HistOpathological Studies..... ...... ........page Case Studies ..................... . ...... ....page Investigations with Salicylate Ototoxicity using Rheumatoid Arthritics... ............. . .......... ...page Tinnitus al‘d PitCh MatCh.......OOOOOOOOOCOOOPage T Statement Of the PrOblem. o o o o 00000 o o o o o o O o o opage EXPERIMENTAL PROCEDURES.....................page SubjectS............ ................ ... ..... page Instrumentation... ....... . ....... ...........page Calibration.... ........ .....................page Procedure ............. . ......... ............page Analysis of Data ........ ....................page RESULTS .......... . ............ ..............page Peripheral Test Results .......... . .......... page Central Test Results .................... ....page 10 13 14 18 22 ‘ 22 23 25 27 35 36 36 44 IV. DISCUSSIONOOOO‘OOOOOO0..........OOOOOOOOOOPa-ge Peripheral Testing.......................page Central Testing..........................page conCluSionS.......OOOOOOOOO‘OOOCOO......OOPage Implications for Further Research........page APPENDICES APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX APPENDIX F: G CASE HISTORY................page PITCH MATCH I ANSWER FORM...page FORM A NORTHWESTERN UNIVERSITY AUDITORY TEST NIMBER SIXOOOOOOOOOOOOOOO...page FORM B NORTHWESTERN UNIVERSITY AUDITORY TEST NUT'TBER SIXoooooooooooucooooOPa-ge FORM D NORTHWESTERN UNIVERSITY AUDITORY TEST NUDiBER SIXOOCOOOOOOOC’OCCCCOPa-ge NOMATIVE DATAOOOOOOOOOOOOOOPag-e BRIEF TONE TRACINGS.........page LIST OF REFERENCES.00.0.0000.........OOOOOOOOOPage 49 49 51 53 54 57 61 63 64 65 67 69 7O TABLE TABLE TABLE TABLE TABLE TABLE TABLE TABLE 1: LIST OF TABLES Pure tone air conduction thresholds tested at 250- 8000 Hz bilaterally. Pure tone average (PTA), speech reception threshold (SRT), percentage correct (%) for Northwestern University Auditory Test Number Six (NU# 6) monosyllables at 40 dB sensation level re: SRT indicated hearing at the lower limits of normal. Results were essentially the same for both test sessions ....................... ........page 36 Results of Carhart Threshold Tone Decay test and masked and unmasked Short Increment Sensitivity Index (SISI)0............OOOOOOOOOOIO......Opage 38 Thresholds for the acoustic reflex for frequencies 500, 1000, 2000, and 4000 Hz. The reflex thresholds are in hearing threshold levels (HTL) and sensation levels (SL) re: pure tone thresholds. Reflex decay values are the time in seconds (SEC) the reflex was maintained ..... ............ ..... ............page 39 Brief tone thresholds computed by averaging the mid- points of the excursions for the frequencies 500, 1000, and 2000 Hz....... ..... . ..... .........page 43 The differences between 500 msec and 20 msec and between 200 msec and 20 msec tones are shown.... ...... ............ ..... ............page 44 Percentage correct for three conditions of time compression (0%, 30%, and 60%)and filtered speech ............ ... ...... ........page 45 Mean, median, mode, range, and differences of scores for ten normal hearing young adUltSOOOO ........ O ........... ......OOOOOOOOpa-ge 46 Responses to two randomizations of dichotic consonant—vowel syllables. Correct responses are noted with an asterisk (*). Total number of correct responses is noted at the bottom of each column ..... . ........ ................page 47—48 LIST OF FIGURES FIGURE 1: Block diagram of instrumentation used for auditory testing..........................page 24 FIGURE 2: Tympanogram shows normal findings of middle ear compliance as air pressure is increased and then decreased in the ear canal.....................................page 40 FIGURE 3A: Normal otoadmittanCe results for the SUbjGCt'S right ear-0......OOOOOOOOOOOOOOOOpage.41 FIGURE 3B: Normal otoadmittance findings for the - subject's left ear ...... ..................pageT42 ii CHAPTER I INTRODUCTION There has been a major interest in the phenomenon of transient hearing loss induced by high levels of salicylate in the blood stream because aspirin is a commonly used non— prescription drug. When high salicylate levels are present, intoxication and subsequent transient hearing loss are said to occur. Investigators have explored the fluctuant hearing loss phenomenon with the goal of discovering the auditory mechanisms involved, whether the hearing loss is temporary or 'permanent, the serum levels for intoxication and subsequent hearing loss, the focus of the action of the aspirin, and the physiologic reactions to salicylates. The purpose of this study was to investigate the effects of salicylate intoxication on the perception of pitch and on cochlear, retrocochlear, and central processes. 'Since the determination of the area or areas affeCted via pitch match tasks would only indicate sensorineural or conductive hearing loss, examination of the learing loss with special auditory tests was warranted to differentiate among cochlear, retro- cochlear, and central sites of lesion. SALI CYLATE OTOTOXI C I TY Early Research In 1903, Wittmaak (as cited in DeMoura and Hayden, 1968) reported on animal research concerning the influence of salicylates and quinine on the auditory system, specifically the cochlea, of the test animals. He noted the disappearance of Nissl bodies and changes in the nuclei of the spiral 'ganglion cells due to quinine. Because he suspected that salicylates acted on the inner ear in a similar manner, Wittmaak concluded that these changes occurred with salicylate poisoning. However, in 1913, Lindt's experimentation with salicylates (as cited in DeMoura and Hayden, 1968) did not -verify Wittmaak's findings. Experimenting with animals, he did not find consistent changes due to aspirin in the cochlear structures of the test animals. The animals used in the pre- vious studies were not specified by DeMoura and Hayden (1968). In an effort to discover additional information about the action of salicylates and quinine upon the meChanisms of the ear, CoVell (1936) administered sodium salicylate and quinine bisulfate to guinea pigs, white rats, and rabbits. He found similar reactions upon the cochlea from both drugs, with quinine being the more pervasive reactant. The temporal bone sections of the experimental group of animals revealed mitochondrial changes in the cochlear duct and a loss of the ground sub- stance in the spiral ganglion, especially in the lower modiolus. Increased protein levels were also observed. Covell also noted pronounced changes in the outer hair cells of the Organ of Corti. The mitochondria, which indicate presynaptic areas, were shapeless and the hair cells themselves were swollen. He attributed mitochondrial abnormalities to direct proto— plasmic poisoning. Further research (Mosher, 1938) found that hemorrhage occurred in the cochlea of guinea pigs as the result of salicylates, but this has been attributed to the temporal bone removal technique then employed (as cited in DeMoura and Hayden, 1968). Fable-Hansen in 1941 (as cited in Waltner, 1955) reported that Reissner's membrane was depressed into the cochlear duct more often after salicylates or quinine injection. He suggested that the cochlear changes were hypotonic in nature, i.e., lower osmotic pressure of the cochlear fluids. But Fable-Hansen noted these findings cautiously because of the inconsistency of the disruptions in the discovered abnormal— ities. Waltner (1955) Speculated as to the possible reaction of the cochlear structure to the salicylates. He hypothesized that the reaction of salicylates on hearing may be due to direct protoplasmic poisoning, to interference with the normal blood supply to the inner ear, and/or to increased intra- labyrinthine pressure. He indicated that the latter hypothesis was the most probable result of salicylate intoxication. Recent Investigations Recent research has not demonstrated permanent structural damage to occur to the stria vascularis, sensory epithelium, spiral ganglion, or cochlear nerve as the result of salic- ylate intoxication. However, deviations do occur that effect the efficiency of the auditory system. Bernstein and Weiss (1967) investigated the effects of salicylate intoxication on rheumatoid arthritics. In the pre- toxic state, hearing for pure tones and speech was within normal limits bilaterally. After administration of the aspirin, mild bilateral symmetrical sensorineural hearing loss was noted. Temporal bone analyses of two patients with rheumatoid arthritis who had ingested large doses of aspirin for long periods of time showed no abnormalities in the hair cells, Organ of Corti. stria vaSCularis, or spiral ganglion. Silverstein, Bernstein, and Davis (1967) reported the re- sults of an experiment with cochlear microphonics and action potentials in cats injected with sodium salicylate. They found an elevation in the threshold of the eighth nerve action po— tential and a decrease in the amplitude and dynamic character— istics of the cochlear microphonics due to high levels of aspirin in the blood stream. Latency of the cochlear micro— phonics did not appear to be affected. Myers and Bernstein (1965) compared audiograms before and during salicylate intoxication of individuals with normal and abnormal hearing. To avoid confusion, hearing threshold levels of this study and the studies following will be discussed re: ANSI 1969. Subjects with normal pre—toxic audiograms exhibited mild bilateral flat sensorineural hearing losses during salic— ylate intoxication. The fourteen subjects with abnormal pre- toxic audiograms were divided into four subgroups: unilateral sensorineural hearing loss, acoustic trauma, high frequency sensorineural hearing loss, and flat presbycusic hearing loss. During salicylate intoxication, subjects with high frequency sensorineural hearing loss and those with acoustic trauma in the pre—toxic state showed an elevation in threshold primarily in the low frequencies at levels of approximately 40 dB HTL re: ANSI 1969 across all frequencies due to aspirin. The subjects with unilateral sensorineural hearing loss were found to have an elevation in threshold in the affected ear and in the better ear across frequencies on the order of 40 dB. The presbycusic subgroup exhibited a symmetrical, flat, bilateral hearing threshold of about 40 dB HTL re: ANSI 1969, an increase of approximately 15 dB from the pre—toxic audiogram. The above studies agreed that salicylates, when given a serum level of about 30 mg./1OO ml., induced inhibitory effects on groups of cellular enzymes. This action produced an un- coupling of oxidative phosphorylation which caused an altera- tion in the biochemical or bioelectric properties within the cochlear duct. This in turn could effect the stria vascularis and the Organ of Corti by decreasing metabolic activity. 'Characteristics of Salicylate Induced Hearing Loss Although there is much disagreement among researchers as to the form of interference and the loci of involvement with— in the auditory system, most investigators have acknowledged a variety of characteristics typically associated with salic- .y1ate intoxication. Tinnitus, hearing loss, and vertigo may all be present in the individual. Once salicylates are with— drawn, rapid recovery of hearing, within 24-72 hours, and disappearance of tinnitus and vertigo are demonstrated in most individuals. With few exceptions (Kapur, 1965; Jarvis, 1965), hearing returns to pre—toxic levels. The hearing loss, in general, is bilateral, sensorineural, symmetric, and equiva— lent over all frequencies for those with normal hearing in the pre—salicylate state. The hearing loss rarely exceeds 40—50 dB HTL, and discrimination scores are depressed. Re— cruitment has been reported, but the method of measurement was not indicated. Cochlear microphonics are depressed and the eighth nerve action potentials are elevated. Attempting to establish whether or not serum levels and amount of hearing loss were related, Myers, et al. (1965), Silverstein, et al. (1967), and Sheffield and Turner (1971) examined the levels of salicylate in the blood stream which preclude involvement of the hearing mechanisms and subsequent hearing loss. Myers, et al., demonstrated that as the plasma salicylate level reached 30 mg./100 ml., a hearing loss of approximately 30—40 dB HTL re: ANSI 1969 was observed. Further increase in serum levels increased the degree of hear— ing loss and related symptoms. So that as serum levels in- creased, elevation in threshold increased but not beyond 50 dB HTL re: ANSI 1969. There no longer was a direct correla-- tion between plasma salicylate levels and the amount of hear— ing loss. Thus, it appears that additional salicylate taken into the blood stream does not continue to elevate hearing thresholds. Investigations conducted by Silverstein, et a1. and Sheffield and Turner concurred with these findings. Therefore, hearing loss incurred appears to be dosage dependent, transient, and may be accompanied by tinnitus and/ -orvvertigo. HistOpathological Studies HistOpathological studies have increaSed the body of knowledge available on salicylates and their effects on the aUditory system. To illustrate the course these studies have taken over the years, the investigations highlighting the re— search in this area shall be discussed according to research methodology. Recent histopathological studies using guinea pigs have not indicated structural abnormality of the Organ of Corti, stria vascularis, or spiral ganglion. Agreement in the as- sumption that salicylate ototoxicity results in uncoupling oxidative phosphorylation in the cochlea lends support to the contention of earlier researchers that the effect on the audi— tory structures is biochemical in nature. Krazanowski and Matschinsky (1971) reported data that revealed the locus of impairment to be in the energy metabolism mechanism of Reissner's membrane. However, Thalman, Miyoski, Kusakari, and Thalman (1973) pointed out that electrophysiological data, specifically the measurement of adenosine triphosphatase, have been limited. Adenosine triphosphatase (ATP) is an eSter con- cerned with energy metabolism for muscular and other cellular activity. Measurement of ATP action at the cochlear nerve via ultramicrochemical techniques during salicylate intoxication led Thalman, et al., to conclude that although there appeared to be an absence of detectable changes in the acoustic nerve and ganglion, the main action of salicylate induced hearing loss may be at the neural level. Support for this assumption can be found in an earlier study conducted by Silverstein, Bernstein, and Davis (1967). Because of a decrement in the cochlear micrOphonic and an elevation in the eighth nerve action potential during salicylate poisoning, they hypothe- sized that high concentrations of salicylate probably produc- ed transitory effects which were inhibitory to the enzyme systems in the hair cells or at the synaptic nerve endings. Therefore, this may indicate a retrocochlear site of action. In Opposition to theSe investigations, McPherson and Miller (1974) determined the focus of the salicylic action to be the cochlea. These researchers assessed the reaCtion of the hearing structures to aspirin via measurement of cochlear po— tentials in guinea pigs. Elevated salicylate levels reduced the amplitude of the first negative peak (N1) and decreased the amplitude, but not the latency, of the cochlear micro- phonics. They concluded that these findings were indicative of inner ear pathology. Gold and Wilpizeski's (1966) results agreed with the con- _clusions reached by McPherson and Miller. When they implanted permanent electrodes into the ears of an experimental group of cats, Gold and Wilpizeski observed reduction in the N1 10 amplitude accompanied by an elevation of 30 dB in N threshold, 1 and a depression of cochlear microphonics. These authors con- cluded that the site of action was intracochlear. The inconclusive nature of the research thus far can be noted in the results of previous investigations. To date, de- termination of the focus of the negative effect of salicylic action has not been resolved. Case Studies Histopathological research has not allayed the confusion nor has it decided the controversy over the loci of involve— ment Of salicylates. To further complicate this discussion, case study investigations have proved to be contradictory and without conclusive evidence as to loci of salicylate action. But discussion of case studies is imperative to understanding the research to date concerning salicylate ototoxicity. In 1960, Kodman, Cull, and Lawson reported on a male patient who sustained a residual bilateral sensorineural hear- ing loss of a magnitude of approximately 80 dB HTL re: ANSI 1969 in the high frequencies. Generally, salicylate induced hearing loss rarely exceeds 50 dB HTL re: ANSI 1969. However, in addition to the salicylates, the patient had also been ex- posed to carbon monoxide. The treatment of exposure to carbon monoxide included chloroquin, a known ototoxic drug. Other ll medications were pabalate H.C. and hydrocOrtizone. Withdrawal of salicylates resulted in improvement of hearing thresholds, leaving only residual bilateral high frequency impairment. The authors cautioned against attributing the sustained hear- loss solely to aspirin because of the inability to disseminate the interactive effects of the aspirin, the other medications, and the carbon monoxide exposure. Kodman, et al. also noted an additional finding: clinical evidence strongly pointed to both a cochlear and a retrocochlear lesion which were at least partially reversible. Bone conduction thresholds and tinnitus they interpreted as indicative of cochlear pathology. However, the scores for speech discrimination did not decrease with in— creased presentation level as would be expected with a cochlear lesion. TJarvis (1965) wrote of a case of severe unilateral sensor- ineural hearing loss possibly related to ingestion of 2-3 tab— lets every two hours for a period othhree days for pain follow- ing a tooth extraction. This resulted in a hearing loss ipsi- lateral to the side of the extraction. Since the subject had not been taking another form of medication previously, salic- ylates were assumed to be the cause of the hearing loss. But, since the hearing loss occurred on the same side as the ex— traction, hyperaemia and pain could have produced reflex neural or circulatory disturbances that in turn modified inner ear 12 blood supply ipsilaterally, thereby resulting in increased susceptability of the hearing structures to the action of the salicylate. Idiosyncratic hypersensitivity to the larger- than-recommended dosage may also have induced the hearing loss. Such an idiosyncratic sensitivity to aspirin was noted by Kapur (1965). Following a febrile illness during which three tablets of the usual strength were ingested, a severe bilateral hearing loss and dizziness occurred in a thirteen year—old patient. Although the origin of the child's hearing loss may be viral due to the fever, case history information, onset, symptoms; absence of upper respiratory symptoms, audio- logic findings and vestibular test results indicated idioSyn— cratic hypersensitivity to acetysalicylic acid. The patient sustained a moderate to severe bilateral sensorineural hear- ing loss. Salicylate induced hearing loss due to topical application was reported by Perlman (1966). Bilateral symmetrical sensor- ineural hearing loss and tinnitus were evidenced in two female patients from skin application of 24—35 mg./100 ml. of salic— ylate for treatment of psoriasis. Termination of salicylate treatments resulted in a return to pre—toxic hearing thresholds. 13 Investigations with Salicylate Ototoxicity using Rheumatoid Arthritics ‘ Research employing rheumatoid arthritic subjects has yielded more information on the possible hearing loss caused by salicylate intoxication. Initially, investigations center- ed around rheumatoid arthritis as a possible cause of conduc- tive hearing impairment due to involvement of the ossicular chain. Although the occurrance of rheumatoid nodules in the middle ear is a possibility, Goodwill, Lord, and Knill Jones (1972) did not find rheumatoid nodules or erosive changes in the ossicular joints in their analyses of temporal bone sections. Djupesland, Grénas, and Saxegaard (1973) performed pure tone air and bone conduction and impedance measurements (tympanograms and acoustic reflex) on rheumatoid arthritics with elevated hearing threshOlds. Test results revealed 'middle ear pressure and compliance of the tympanic membranes in general to be within normal limits. The stapedial reflex was present. These results indicated a normally functioning middIe ear. These authors concluded that although conductive pathology is possible in rheumatoid arthritics, their Subjects did not demonstrate middle ear involvement. Bernstein and Weiss (1967) examined auditory sensitivity in individuals taking salicylates for treatment of rheumatoid arthritis. They found central summation to be intact and a 14 depression of caloric function, as ascertained by the Hallpike bicaloric technique. They concluded that the action was peri— 'pheral and not central in nature. The previous review has demonstrated the inconclusive and contradictory nature of the research in this area. Histologi- cal, audiologic and biochemical studies have yielded some in- formation, but knowledge is still lacking concerning the loci of involvement. Covell (1936) stated, "the effects of various toxic agents such as drugs, poisons, and toxins on the meChan- isms of hearing are more readily studied by tests of hearing than by examination of sections of the cochlea for pathologi— cal changes"(p. 633). Clinical tests of suprathreshold hear- ing function, examination of the acoustic characteristics of tinnitus, and tests of central auditory function may prove to be mOre sensitive indicators of salicylate intoxication, and may provide information as to the specific areas of the audi— T tory system involved. TINNITUS AND PITCH MATCH Tinnitus has long been recognized as an indicator or symptom of otologic dysfunction (Graham and Newby, 1962). Tinnitus is a common occurrance with salicylate intoxication (Kapur, 1965). In many cases it was the firSt symptom ex- 'perienced by the patient (Jarvis, 1965). Various authors 15 have discussed the subjective appraisal of the tinnitus ex- perienced. Some have described the tinnitus as being high pitched and others have depicted the tinnitus to be a "buzz" or a "roar” or musical notes. Determination of theSe des— criptions or terms was not given by the investigators. In— dividual patient subjective classification most probably accounted for the variety in the reports. Graham and Newby (1962) investigated the acoustic char-T aeteristics of tinnitus in an attempt to establish a basic method for analyzing non—vibratory tinnitus and to determine whether differences among pathological populations existed. By employing subjective reports, initial and final pitch matches, and loudness judgments, these authors found a dif- ference among pathological states. The results of this study indicated that individuals with sensorineural hearing losses with tinnitus tend to match their tinnitus to high frequency tones, whereas those with conductive pathology did not match their tinnitus to frequencies greater than 1400 Hz. Graham and Newby concluded that the tinnitus experienced with a con- ductive hearing loss may be the product of a different physio- logical mechanism than that associated with sensorineural path— ology. l6 Nodar and Graham (1965) continued exploration into the possibilities set forth by Graham and Newby. They noted that with Meniere‘s disease, a cochlear pathology, a "buzz" or "roar" was the discriptive classification of the tinnitus per— ceived. Replicating Graham and Newby's experimental design for a pitch match, their findings confirmed Graham and Newby's results. Conductively hearing impaired subjects matched their tinnitus to the frequency range of 90 to 1450 Hz, with a median frequency of 490 Hz. The subjects in the sensorineural group, excluding those with Meniere's disease, compared their tinni- tus to the freqUencies 545-7500 Hz, with a mediam frequency of 3900 Hz. However, these with Meniere's disease associated their tinnitus to the frequency range of 90 to 900 Hz exclusive- ly.‘ The median frequency for this group was 320 Hz. 1 Thus, subjects with Meniere's and those with conductive impairment appear to experience a similar representation of tinnitus although the etiologies are not alike. Nodar and Graham speculated that similar physiologic mechanisms cause the tinnitus that accompanies these hearing disorders. Therefore, via a tinnitus pitch match, information is available which allows differentiation between hearing losses which are conductive in nature from those that are sensor- ineural. But, when patients with Meniere's disease are con- sidered, results of a pitch match are not commensurate with 17 those generally found in sensorineural populations. This may also be true with those individuals experiencing tinnitus as the result of salicylate intoxication. The enzyme actions and/or intralabyrinthine pressure may be affected in a manner _ which inhibits the normal conduction of the cochlear fluids. A comparison of the tinnitus reported by the subject with high serum salicylate levels anthhe data presented by Graham and Newby could yield additional information as to the action salicylates have upon the auditory system. A low frequency pitch match may be indicative of an inner ear conductive action, such as that hypothesized by Nodar and Graham to occur in patients with Meniere's disease. Since biochemical and histOpathological studies have been inconclusive in determina— tion Of site of salicylic action, a pitch match may yield more complete data and understanding of transient hearing loss that occurs during salicylate intoxication.. As Covell (1936) ex— plained, tests of hearing may prove to be the preferred method of examining the effects of drugs upon the auditory system. Therefore, he felt that clinical tests investigating hearing function may be more sensitive measures of salicylate toxicity. The literature in the area of audiologic exploration of salicylate ototoxicity is limited. From the preceding review of the research it may be assumed that more study is warranted. 18 Covell (1936) and McPherson and Miller (1974) called for in- vestigations using audiological assessment, yet the bulk of the research conducted in the intervening 38 years follow— ing Covell's suggestion has been filled with an abundance of biochemical and histopathological studies. All of these ex— periments have left us without definitive answers concerning salicylic action on auditory functioning. STATEMENT OF THE PROBLEM Additional investigation of the effect of salicylates on the auditory system is necessary and the mode of exploration should be with audiologic tests. A pitch match and sophis— ticated audiometric tests will assist in better understanding of the reaction of the auditory system to elevated salicylate levels. Although the literature employing special audiometric test procedures is limited, some researchers have given con- sideration to audiologic testing. Pedersen (1974) limited his experiment to brief tone audiometry on fourteen individuals with salicylate intoxication. His results were indicative of cochlear pathology. Unfortun- ately, other special auditory test were not performed. A pitch match may also furnish data concerning site of salicylate action in the auditory system and the form the 19 action takes on this system. The results of this analysis can then be employed in the area of speculation as to which of the following hypotheses is the force of action during salicylate intoxication: interference with intralabyrinthine fluid con— duction or enzymatic inhibition at the neural level. Additional study is called for. Perhaps new information regarding salicylates and hearing will not surface. But an increase in knowledge, understanding, and awareness of coche lear, retrocochlear, and central processes will certainly be realized. Expanded examination of this subject is therefore imperative. The question under Consideration in this study is: to what frequency does the individual undergoing salicylate in- toxication match the tinnitus he perceives and what information will special test procedures yield regarding cochlear, retro— cochlear, and central auditory function? Bernstein and Weiss (1967) used Bekesy audiometry in audio- logic examination of patients with high serum salicylate levels. Their subjects did not exhibit abnormal tone decay as measured by this procedure, that is a separation greater than 20 dB (Jerger, 1960). Sanders, Josey, and Glascock (1974) have demonstrated that Bekesy audiometry is not the best indicator of abnormal adaptatiOn to acoustic stimuli because the stim— ulus is constantly changing over time. For this reason, they 20 explained that measurement of abnormal tone decay via Bekesy does not stress the auditory system as do other tests for tone decay, e.g. Carhart Threshold Tone DeCay test (Carhart, 1957). In fact, they found that in a great number of cases erroneous conclusions were made on the basis of Bekesy trac- ings alone. An earlier study by Rosenberg (1972) also stress- ed the necessity of obtaining samples of auditory behaviOr that were correlated. He explained that the diagnosis of auditory disordercannot be made on the findings of a single test. In- stead, a test battery approach is preferred and advocated. With this in mind, the present knowledge of special tests and procedures can and mUst be used with individuals under~ going salicylate intoxication. Applying a test battery con- sisting of peripheral and central auditory tests, and an analysis of the perceived tinnitus to the population of rheumatoid arthritics undergoing salicylate intoxication will increase our knowledge of salicylic effect on the auditory system-—peripheral and central aspects. Pitch matches may also furnish data concerning site of salicylate action in the auditory system and the form the action takes on this system. The results of this analysis can then be employed to speculate as to which of the follow— ing hypotheses is the force of action during salicylate in— toxication: interference with intralabyrinthine fluid 21 conduction or enzymatic inhibition. The questions under consideration in this study were: 1) 2) to what frequency does the individual under- going salicylate intoxication match the tinnitus she perceives? what information will special test procedures yield regarding cochlear, retrocochlear, and central auditory function? CHAPTER II EXPERIMENTAL PROCEDURES Subject The subject taking part in this study was selected on the basis of experiencing tinnitus while using salicylates. To achieve an optimum effective anti-inflammatory level, serum salicylate levels of at least 15 to 30 mg./100 ml. must be reached (Mongan, Kelly, Nies, Porter, and Paulus, 1973). Since tinnitus and hearing loss can be seen at levels of 30 mg./ 100 ml. on the average, this subject was chosen. Hearing loss due to salicylates was not a requisite for inclusion in this study. The subject was a 39 year-old white female. Case history information was unremarkable with the exception of daily in- gestion of 19-20 aspirin tablets for treatment of rheumatoid arthritis. There was no history of middle ear infection or other otologic disorder (See Appendix I). Ten normal hearing young adults ages 17-23 years of age were evaluated to establish normative data for the filtered speech used in this study. Hearing was screened at 15 dB 22 23 HTL re: ANSI 1969 for the frequencies 250-8000 Hz. Speech reception thresholds and word disCrimination scores were es- tablished prior to testing with filtered speech. Different forms of the Northwestern University Auditory Test Number Six were administered in the filtered and unfiltered conditions. Instrumentation Audiometric equipment consisted of a Grayson-Stadler 1701 clinical audiometer for routine and special testing and the initial pitch match; a Grayson—Stadler 1720—B Otoadmittance meter and Madsen ZO—70 Impedance bridge (coupled to a Beltone lO—C portable audiometer) for tympanometry, stapedial reflex measurement, and reflex decay; a Grayson~Stadler 1701 X—Y re- corder for graphic representation of brief tone thresholds; a Hewlett—Packard 3310-A function generator for continuous frequency adjustments during the final pitch match; a Beckman 6148 frequency counter for frequency assessment during the final pitch match; a Grayson-Stadler 1208 power supply, switch and timer for variable stimulus duration for brief tone audio- metry; a Sony TC 366 two-channel tape recorder for routine speech audiometry and tests of monotic and dichotic listening ability; and a matched set of TDH—49 earphones in MX 4l/AR cushions (See figure 1). 24 .mcflummv whoufipsm Mom wows coaumucmfisnumcfl mo EMHUMAU xuoam “H munmflm Ilulll T11: eloamm omEMOENIBquzmm moefimmZmO ZOHEUZDM m 4 xx N NT ETTNmMN N .\ \» _~‘.\T1\ T \1 x. \x \V .\ATI\ CTT.\T \\ a mVHm Zdzxumm mmezooo _ wozmsommm Te T Hona oemuoe Azom meanesmnzomweme mmomoomm mmemsoHooe HOSH me wees aeonqu _ mnemoomm qmzzamo ose rill: wux I .T u mnomna mo m emm hmma mm mmsz mesa: _ tzomemqme IIIIIL mmoomoanomo eloama mo mosHSM mozeestoaoso mONH mm Mammbm MMBOm I All 25 Calibration Additional equipment was used for general calibration purposes and for calibration of the instrumentation used to filter a taped reproduction of the Northwestern Auditory Test Number Six (NU#6) Forms A and B (Tillman and Carhart, 1966). Calibration consisted of Random Sine Generator (Bruel and Kjaer type 1024); a Frequency Spectrometer (Bruel and Kjaer type 2112); a graphic level recorder (Bruel and Kjaer type 2305); an Oscilloscope (Teletronix 564-B); and a Spec— trum Analyzer (Teletronix 3L5). A tape of filtered speech was made by reproducing the NU#6 Forms A and B on an Ampex AG 402 two-channel tape re— corder and then feeding the output through a General Radio 1925 Multifilter One-third Octave and Band Filter with re- lated switch assembly. The rejection rate was 32 dB in the first octave with no measureable output at 1000 hertz (HZ) and the cut-off frequency was 500 Hz (Lynn and Gilroy, 1972). The filtered speech was recorded on Scotch AV 176 low noise oxide recording tape with the Ampex AG 440 two—channel re— corder. Signal intensity of the Grayson—Stadler 1701 clinical audiometer for routine and special testing and the pitch matches and the Beltone lO-C portable audiometer for acoustic reflex and reflex decay testing was in accordance with the 26 specifications of the American National Standards Institue (ANSI 83.6 1969). Intensity calibration was checked with an input of 70 dB HTL at the eleven frequencies. Appropriate corrections were made where necessary. Deviation of the sound pressure level reading from the hearing threshold level dial by more than 3 dB at the frequencies of 250 to 3000 Hz inclusive, by more than 4 dB at 4000 Hz, or by more than 5 dB at the frequencies above or below this range indicated that a correction was to be made. Linearity was measured at 1000 Hz by starting at the limits of the audiometer (110 dB HTL) and descending in 5 dB steps. Linearity did not differ from the dial reading by three—tenths of the dial setting or 1 dB, whichever was larger (ANSI, 1969). These measurements were made for both earphones with a Bruel and Kjaer type 4152 artificial ear using a Bruel and Kjaer type 4144 pressure microphone attached to a Bruel and Kjaer type 2204 sound level meter. Frequency output on the Grayson—Stadler 1701 and the Belton lO-C audiometers was checked with the Beckman Fre— quency Counter (6148). Frequency output for 125—8000 Hz was found to be within i 3% of the given frequency. Speech was calibrated with each tape by the 1000 Hz calibration tone on the individual tapes. Complete cali- bration for speech was made prior to testing by directing 27 the speech signal through the test earphones to an artificial ear (Bruel and Kjaer type 4152) with pressure microphone (Bruel and Kjaer type 4144) coupled to an Audio-Frequency spectrOmeter (Bruel and Kjaer type 2112). Rise-decay time and on-time duration were checked for the SISI. The rise—decay time was found to be 50 msec, and the duration of the tonal stimulUs was 200 msec. These are in accordance with Jerger's (1960) recommendations. The possibility of spread of energy to frequencies other than the test frequency during brief tone audiometry was assessed with the Teletronix 3L5 Spectrum Analyzer coupled to the Teletronix 564 OscillOSCOpe. Energy was 44 dB or more be- low the fundamental frequency for the second and third harmon- ics at the frequencies 500, 1000, and 2000 Hz at 500, 200, and 20 msec. Procedure The subject was seen on two occasions, During the first session, pure tone air conduction, speech reception testing (SRT), word discrimination, SISI (at high and low sensation levels), brief tone audiometry, otoadmittance, impedance, tone decay, and the pitch matching tasks were performed. In the second session, pure tone air conduction, SRT, word discrim- ination, SISI (at high and low sensation levels), tone decay 28 and impedance were readministered. At this time central test— ing of hearing at the cortical level was also administered. Hearing sensitivity of the ten normal hearing subjects was screened at 15 dB HTL re: ANSI, 1969 for the,firequencies 250 to 8000 Hz. Speech reception threshold, unfiltered and filtered word discrimination ability were assessed. Three tests were routinely Used to assess hearing for both ears: pure tone air conduction testing, speech reception thresh- old determination, and word discrimination testing. Special peripheral test procedures were employed to eval- uate the site of lesion for both ears. They were the Carhart threshold tone decay test, the Short Increment Sensitivity Index (SISI) at low and high sensation levels, brief tone audiometry, otoadmittance and impedance audiometry._ ‘Two pitch matching tasks were made for both ears. The first match was performed with the audiometer to establish an estimate of the range of frequencies which approximated the tinnitus experienced by the subject. TA second pitch match was made with the Hewlett Packard 33lO—A function generator which allowed for a continuous change in frequency over the entire audible frequency range. This provided a finer es- timate of the frequency analogous to the tinnitus. The test battery for central auditory function consisted of time compressed Northwestern University Auditory Test NUmber Six (NU#6), Staggered Spondaic Words (Katz, Basil, and Smith, 1963), low-pass filtered speech (Lynn and Gilroy, 1972), and simultaneous dichotic Consonant—Vowel (CV) 30 The instructions were: You will be hearing some words. The words are: airplane, armchair, baseball, birthday, cowboy, daybreak, doOrmat, draw- bridge, duckpond, eardrum, farewell, grand— son, greyhound, hardware, headlight, horse— shoe, hotdog, hothouse, iceberg, inkwell, mousetrap, mushroom, northwest, oatmeal, padlock, pancake, playground, railroad, schoolboy, sidewalk, stairway, and white- wash. Repeat the words after the gentle- man on the tape, no matter how soft the words may become. Discrimination for speech under earphones was assessed monaurally for both ears at 40 dB senSation level (SL) re: SRT. The speech stimuli were taped lists of the N.U. #6 form D (Carhart and Tillman, 1966). The subject was told: You will be hearing some sentences. These will not decrease in loudness. Please repeat the last word in each sentence after the gentleman on the tape. For example, if he says, You will say, 'black', all you must repeat is the word "black". Do you have any questions? Tone decay was measured via the Carhart Threshold Tone Decay test (Carhart, 1957). The tone was presented at 500 and 2000 Hz at pure tone threshold. The subject was instructed: Once again you will be hearing a tone. This time I want you to press the button down when you hear the tone and keep the button depressed as long as you hear the tone. Should the tone disappear, be prepared, it may become audible again. 31 The SISI (Jerger, Shedd, and Harford, 1959) was assessed at 20 dB SL the pure tone threshold at 500 and 2000 Hz. The subject was required to respond when an increment in the test signal was heard. The test procedure was then repeated at a higher sensation level of 75-80 dB to evaluate possible re— trocochlear involvement. Thompson (1963) reported that when the SISI was presented at high Sensation levels those with normal hearing evidenced high or positive SISI scores whereas individuals with retrocochlear pathology continued to show low or negative SISI scores. The instructions were: IYou will be hearing a tone continuously. This tone will "jump“ in loudness at various intervals. Each time you hear the "jump" in loudness, please depress the button. Are there any questions? ‘Brief tone audiometry was administered at 500, 1000, and 2000 Hz. Research indicated that normal ears integrate acous- tic energy in a near linear function at these frequencies (Wright, 1968). Thresholds were obtained at these frequencies using durations of 500, 200 and 20 msec with a rise—decay time of 10 msec. Bekesy tracings were obtained and the subject was told: You will be hearing pulsed tones. Depress the button as long as you hear the tones and release the button when you can no longer hear the tones. 32 At the end of testing with brief tones a tracing with a con- tinuous tone was made to yield additional information. The subject was reinStructed with the standard directions; how- ever, instead of a pulsed tone the subject was informed that she would be hearing a continuous tone. The same frequencies were evaluated. . Tympanograms for both ears were obtained via otoad- mittance and impedance audiometry. Reactance and suscep— tance measures were made using 220 and 660 Hz tones with the iotoadmittance meter. The threshold for the acoustic reflex and reflex decay were evaluated on the impedance bridge. Re— flex decay was tested at 500 and 1000 Hz because considerable decay had been found in normals-at 2000 and 4000 Hz (Anderson, Barr, and Wedenberg, 1970). .The subject was told: For this test, all you must do is sit quietly. Please do not talk or swallow. What you will be feeling is air being put into your ear canal and then withdrawn. The initial pitch match was administered with a clinical audiometer. Using the eleven available frequencies, each fre— quency was presented twice at 10 dB SL re: pure tone thresholds. 32 At the end of testing with brief tones a tracing with a con- tinuous tone was made to yield additiOnal information. The subject was reinstructed with the standard directions; how- ever, instead of a pulsed tone the subject was informed that she would be hearing a continuous tone. The same frequencies were evaluated. Tympanograms for both ears were obtained via otoad- mittance and impedance audiometry. Reactance and suscep— tance measures were made using 220 and 660 Hz tones with the otoadmittance meter. The threshold for the acoustic reflex and reflex decay were evaluated on the impedance bridge. Re- flex decay was tested at 500 and 1000 Hz because considerable decay had been found in normals at 2000 and 4000 Hz (Anderson, Barr, and Wedenberg, 1970). The subject was told: For this test, all you must do is sit quietly. Please do not talk or swallow. What you will be feeling is air being put into your ear canal and then withdrawn. The initial pitch match was administered with a clinical audiometer. Using the eleven available frequencies, each fre- quency was presented twice at 10 dB SL re: pure tone thresholds. 33 The subject was instructed: You will be hearing some tones. I would like you to listen to the tones. They will be preSented twice. After the second presenta— tion, please mark the sheet of paper in front of you as to whether the tone was higher, lower, or equal to the noises in your ears. The preceding results were analyzed following a five minute rest period. This yielded a frequency range which the subject judged as equal to the perceived tinnitus. The final pitch match was then made with the function generator at 10 dB SL re: the average threshold for this frequency range. 'The subject was told: With the white dial in front of you, please vary the pitch by turning the dial. First make the tone noticeably higher in pitch, then lower in pitch than the noises in your ears. Finally, I want you to make the tone equal to the noises in your ears. Three trials were given for each ear and each was evaluated monaurally. The average of the three trials was taken as the frequency match of the tinnitus. Time compressed Northwestern University Auditory Test Number Six (Beasley, Schwimmer, and Rintelmann, 1972) were administered monaurally at 0%, 30%, and 60% compressiOn. The word lists were presented at 40 dB SL the patient's monaural SRT. The subject was instructed in the same manner as for word discrimination testing for this and filtered speech. 34 Discrimination of low pass filtered speech (Lynn and Gilroy, 1972) was evaluated at 60 dB SL monaural SRT. The cut-off frequency was 500 Hz with a rejectiOn rate of 32 dB in the first octave. Different forms of the Northwestern University Audi- tory Test Number Six were used for the time compressed monosyllables and the filtered mOnosyllables. Word discrim- ination was assessed with form D. Form A was used for the low pass filtered speech test. Finally, form B was used in testing discrimination for speech under various conditions of time compression. The Staggered Spondaic Word test (Katz, Basil, and Smith, 1963) was presented dichotically at 50 dB SL re: SRT.’ The subject was instructed: You will be hearing some two syllable words. Please repeat the words after the gentleman on the tape. Dichotic consonant-vowel (CV) syllables (Berlin, Lowe, Thompson, and Cullen, 1968) were administered simultaneously with no lag time between ears. The preSentation level was 50 dB HTL. The subject was instructed in this manner: You will be hearing some single syllables. I want you to repeat the syllables you hear after the gentleman on the tape. 35 Analysis of Data The results of this study were analyzed quantitatively. Data obtained from the pitch match was compared to the cate- gories established by Graham and Newby (1962) and Nodar and Graham (1965). On the basis of the hypotheses that the hear- ing loss and tinnitus caused by salicylates may be due to increased intralabyrinthine preSsure (Waltner, 1955) or may be due to enzyme inhibition (Myers and Bernstein, 1965), the SUbject undergoing salicylate intoxication was expected to match her tinnitus to the same frequency range as those with conductive pathology or Meniere's disease (Nodar and Graham, 1965). T The peripheral and central test results were interpre- ted with respect to site of lesion. The resultswere examined in order to obtain a better understanding of the cochlear, retrocochlear, and central processes of the ear during salicylate intoxication. - Data obtained for the ten normal hearing subjects for low pass filtered speech was analyzed by measures of central tendency. The mean, median, mode, and range were calculated. CHAPTER III RESULTS Peripheral Test Results Results of puretone air conduction audiometry using pulsed tones of 500 msec with a 50% duty cycle indicated hearing to be at the lower limits of the normal range bilat- 'erally (Davis and Kranz, 1964). Speech reception testing (SRT) was eight decibels (dB) better than these results. This inconSistency may have been the result of the tinnitus interfering with the pure tone thresholds but not with the speech stimuli. Speech discrimination under earphones at 40 dB sensation level (SL) re: SRT was excellent for both ears. (See Table 1) Table 1: Pure tone air conduction thresholds tested at 250-8000 Hz bilaterally. Pure tone average (PTA), speech .reception threshold (SRT), percentage correct (%) for Northwestern University Auditory Test Number Six (NU # 6) monosyllables at 40 dB sensation level re: SRT indicated hearing at the lower limits of normal. Results were essen— tially the same for both test sessions. EAR 250 500 1000 2000 4000 8000 PTA SRT % LIST R 25 20 2O 15 2O 3O 18 10_ 100 NU#6 L 25 20 .20 15 30 30 18 10 100 NU#6 36 37 Although hearing was within normal limits bilaterally, the thresholds were at the lower limits of normal. A battery of sophistocated audiometric tests were employed to further evaluate the effects of aspirin on the auditory system. The Carhart Threshold Tone Decay test was not indicative of abnormal adaptation for either ear. In the left ear, 5 dB or less of tone decay was seen for the frequencies 500 and 2000 Hz. The right ear did not evidence any tone decay for the two test frequencies. (See Table 2). The ShOrt Increment Sensitivity Index (SISI) was ad- ministered at 20 dB SL and 80 dB SL reza pure tone threshOlds for the frequencies 500 and 2000 Hz at low and high sensation levels. At low sensation levels, the SISI was negative, i,e,, notindicative of cochlear pathology, bilaterally. .Inad- vertently, testing at 80 dB SL was initially conducted with- out masking. Since the subject returned for additional evaluation, the SISI was readministered with masking contra- ’1ateral to the test ear. The test results with and without masking revealed positive SISI scores for both ears. These results (see Table 2) were not consistent with retrocochlear pathology (Thompson, 1963). 38 Table 2: Results of Carhart Threshold ToNe Decay test and masked and unmasked Short Increment Sensitivity Index (SISI) RIGHT EAR 500 Hz 0 dB LEFT EAR CARHART TONE DECAY 500 Hz 0 dB 2000 Hz 0 dB 2000 Hz 5 dB LOW 500 Hz 5% 500 Hz 15% unmasked 2000 Hz 0% 2000 Hz ”5% SISI . HIGH 500 Hz 100% 500 Hz 100% 2000 Hz 100% 2000 Hz 100% masked HIGH 500 HZ 100% 500 HZ 80% 2000 Hz 100% 2000 Hz 100% The preceding test results do not demonstrate cochlear or retrocochlear lesion. In fact, examination of these findings portrayed the auditory system as normal since there was no sig- nigicant adaptation and no increased sensitivity to small changes in intensity. The slope of the tympanograms for impedance and oto- admittance were within normal limits for both ears. Eardrum compliance was 0.4 cc in the right ear and 0.39 cc in the left ear. These results demonstrated normal eardrum mobility bilaterally, The acoustic reflex was present at all frequencies tested for both ears and elicitation levels were not elevated. 39 These results showed that middle ear integrity was intact bilaterally. The stapedial reflex was sustained at 500 and 1000 Hz in both ears for 10 seconds. This Was not consis- tent with retrocochlear pathology (Anderson, Barr, and Wedenberg, 1970). (See Table 3) Table 3: Thresholds for the acoustic reflex for frequencies 500, 1000, 2000, and 4000 Hz. The reflex thresholds are in hearing threshod levels (HTL) and sensation levels (SL) re: pure tone thresholds. Reflex decay values are the time in seconds (see) the reflex was maintained. PROBE TONE TE ST TONE EAR - EAR 500 Hz 1000 Hz 2000 Hz 4000 Hz ' HTL 90 dB 85 dB 85 dB 105 dB __Jt_____E_ecjg___J§l__Jg___fi§___ HTL 85 85 90 110 __L___LiLQ_*£L__E__E__ R sec 10 10 REFLEX DECAY L sec 10 10 Graphic representation of impedance and otoadmittance results can be found on figures 2 and 3 (A and B) and show normal middle ear pressure and eardrum mobility. rnobHe stifr I l —T I II I l 0 0 TI 2 2 4 4 5 . fii'i’: 6 A; TTTTTT T ”it-n 8 8: , 3%wflw EN. 1. 7 T Nita. I I ' - TYMPANOGRAM -250 -150 '—50 04-50 -400 -300 ~200 -100 .‘0 +100 +200 air pressure in mm of water Figure 2: Tympanogram shows normal findings of middle ear compliance as air pressure is increased and then decreased in the ear canal. 40 wmpma 10 away Idwoo MILLIMHOS um CON . .nmw unmfln mfluomnnsm map mom muasmmn Tocmuuflaemouo Hmanoz “dim wnsmfim ONIEE mmammmma 00? 0 corn com: on SOHWI'T'TIW 41 MILLIMHOS em .umw puma m.uownnnm mg» How mmcflpcflm mucmuufiapmouo HMEHOZ “mum Tnsmflm ONIEE mmammmma com cow 0 corn com: on SOHWI'T'IIW 42 43 Brief tone audiometry was conducted at 500, 1000, and 2000 Hz at 500, 200, and 20 msec durations (Wright, 1968). Integration functions were found using Bekesy tracings for each test frequency by comparing the midpoints of theexcur- sions for each duration (See Table 4). Table 4: Brief tone thresholds computed by averaging the midpoints of the excursions for the frequencies 500, 1000, and 2000 Hz. ‘ RIGHT EAR msec 500 Hz 1000 Hz 2000 Hz msec .500 Hz 1000 Hz 2000 Hz .209 _ .12 9.13. _ _ .6. EB. _ _1_5_d§ _ 20.9 -1922. 51322.1 SB. 32.27312 _2_0.g__15____2___.12___209__2.1._1.__22_._5___25_.__ 20 20.8' . 13 20 20 26.1 24.5 30 The differences between the long and short durations were approximately 6 dB for the right ear and approximately 5 dB for the left ear. (See Table 5). An ear without cochlear lesion is expected to demonstrate a 10 dB increase in threshold as the stimulus duration is decreased by a factor of 10 (Pedersen, 1974). This pattern of energy integration has not been observed in individuals with cochlear lesion. Persons with inner ear disorder display an integration function of less than 10 dB when stimulus duration is decreased by a factor of 10 (Harris, Haines, and Myers, 1958). 44 Table 5: The differences between 500 msec and 20 msec and between 200 msec and 20 msec tones are shown. RIGHT EAR LEFT EAR msec 500 Hz 1000 Hz 2000 Hz msec~ 500 Hz 1000 Hz 2000 Hz 502-20_7_._2_dE _ _ _7_d_B_ __ _ .5. 51.1.: 509—20_7_._4_d13. _ .31. .21 91B. 5.. 5.2.5113 202-20_4_._2 _____ 4_____§___20.g-_2_0_5____2___§.___ AVERAGE 5.7 5.5 6.5 AVERAGE 6.2 2.9 5.31 The initial pitch match task resulted in a bracketing of the frequency range in which the final pitch match task could be cenducted. The range for both ears was 1000 to 4000 Hz. The final match consisted of an averaging of three separate trials for each ear. Testing both ears in this manner served as a reliability check for each ear. For the right ear the three trial average was 1425 Hz. The trials for the left averaged 1365 Hz. These frequencies coincide with the same category as those with conductive hearing loss (Graham and Newby, 1962: Nodar and Graham, 1965). The right ear was, however, at the upper limits of the conductive range. The pitch match tasks for both ears did not coincide with the frequencies matched by the subjects with Meniere's disease. Central Test Results Time compressed Northwestern University Auditory Test Number Six, Form B (Tillman and Carhart, 1966) was administer- ed at 0%, 30%, and 60% time compression. At 0%.and 30%Ttime 45 compression, discrimination scores were 100% bilaterally. In the 60%.time compression condition, discrimination for speech was 86%»for the right ear and 84% for the left ear. Poor discrimination under extreme levels of time compressiOn was not observed. Therefore, these results were not indicative of central auditory lesion because individuals with lesion demonstrate very poor discrimination in the 60% time compressed condition. - The Northwestern University Auditory Test Number Six Form A was filtered to pass all frequencies below 500 Hz and to cut all those above 500 Hz. The rejection rate was 32de in the first octave (Lynn and Gilroy, 1972) with no measurable response at 1000 Hz. Speech discrimination in this condition was 28%»and 18% for the right and left ears respectively. This resulted in a 10% difference between ears, and was considered a significant difference. Since the task was thought to be difficult for normal listeners, a group of normal hearing young adults was also tested. (See Table 6). Table 6: Percentage correct for three conditions of time compression (0%, 30%, and 60%) and filtered speech. PERCENTAGE . FILTERED TIME COMPRESSION 0% _ 30% 60% SPEECH RIGHT EAR ‘ 100% 100% 86% RIGHT EAR 28% LEFT EAR 100%. 100%» 84% LEFT EAR 18% 46 Findings indicated that normal hearing subjects scored below the norms established by Lynn and Gilroy. All subjects scored well below the range of 40 to 72% correct. Twenty percent of the subjects exhibited a difference between ears of 8%.or more. (See Table 7), TherefOre, a normal hearing population found this task to be difficult. The efficacy of this test with 32% rejection rate for identification of central auditory disorders appears to be too difficult since individ— uals without temporal lobe lesion perform poorly on this test. Table 7: Mean, median, mode, range, and differnces of scores for ten normal hearing young adults. MEAN._ __ __ __ __ MEDIAN__ RENEE __ PlFEEREECE ... MQDL __ ._ All ears: 17.3%? 16% 8—32% ------ .-- 2%P-2 4%--3 Right ears: 16% 16% 8—26% 5.4% 6%——3 8%--l Left ears: 18.6%. 16% 8-32%. , 5%. 12%P-l The Staggered Spondaic Word test (Katz, Basil, and Smith, 1963) was another test used to identify central auditory lesion. The subject showed less than 1% total SSW error (0.86%). This indicated that a temporal lobe disorder did not appear to exist in this subject as measured by the Staggered Spondaic Word test since the competing speech signal did not interfere with discrimination. 47 Dichotic listening ability was assessed with the Simul- taneous Dichotic Consonant—Vowels (Berlin, Lowe, Thompson, and Cullen, 1968). Two randomizations were given to the subject. Hemispheric dominance was not demonstrated. An equal number of responses were obtained for each ear with both randomizations. (See Table 8). Table 8: Response to two randomizations of dichotic consonant- vowel syllables. Correct responses are noted with an asterisk(*). Total number of correct responses is noted at the bottom of each column. RANDOMIZATION I J RIGHT EAR JLEFT EAR RIGHT EAR LEFT EAR *pa rba ga *ka *ka pa *ta *pa *ga ta ta *ga *da pa *da ' ga *ka da da_ pa ba ta pa *ba ga pa ba *ta da *ga *ba *ga ba *ka pa ba pa ' *da ' *ka *ba *ba ga *ba pa *pa ga ga pa ta ba ga *ba ka *ga ga ta *ka ta da *ba ta *da *ga da ga *ka *ka ta *ta pa *ba' *da ba pa ba *ka da *ka *ka ‘da ta ga da *ka ga ' ba *ka pa da ta pa ga ka *ba *ta *ba Table 8: (continued) 48 RANDOMI ZAT I ON RIGHT EAR LEFT EAR RIGHT EAR LEFT EAR *ga da *ta da *da *ba *ta ka pa ka *ka *ga ta *ka . *pa *da *ba *da *pa *ta' pa *ta da ta TOTAL 12 12 16 16 CHAPTER IV. DISCUSSION Peripheral Testing The subject exhibited peripheral hearing that was at the lower limits of normal hearing (Davis and Kranz, 1964). The subject reported noticing a decrement in acuity following treatment for rheumatoid arthritis which consisted of a daily intake of 19-20 aspirins. Although the routine test battery consisting of puretone air conduction threshold determination, speech reception threshold determinatiOn, and word discrimin- ation testing indicated hearing to be within the normal range, the subject did report difficulty with her hearing and com- plained of continuous tinnitus. I With the exception of brief tone audiometry, the peri- pheral auditory test battery did not indicate cochlear or re- trocochlear involvement. Tone decay and SISI testing, at high and low sensation levels, suggested a normally function- ing inner ear and retrocochlear processes. Normal middle ear integrity was confirmed by impedance and otoadmittance measures. Therefore, even with a complete test battery as complete as this, no of site of lesion could be determined in this individual with borderline normal hearing. However, 49 50 brief tone audiometry either appeared to be a more sensitive measure for an individual with hearing at the lower limits of normal hearing or was the unusual finding since it was the sole indicator of cochlear site of lesion. The ear integrates energy below critical duration in logarithmic manner in the subject withoUt cochlear pathology. Decrement Of stimulus duration by a factor or 10 result; in an elevation in threshold of 10 dB. BUt, persons with cochlear lesions integrate energy by a smaller factor (Garner, 1947). In this subject, decrement in stimulus duration resulted in an increment in threshold by approximately 5—6 dB, an increase similar to that seen in patients with cochlear disorder. These results are consistent with those found by Pedersen(l974) in a population of rheumatoid arthritics undergoing salicylate intoxication. Thus, even though other test procedures did not reveal a site of lesion, brief tone audiometric results did suggest cochlear site of action. Information regarding salicylic action on the auditory system was not definitive as the result of the pitch match task findings. This subject matched the tinnitus perceived to the frequencies 1365 and 1425 Hz. Comparison of these findings with those of Graham and Newby (1962) and Nodar and Graham (1965) shows that this subject appears to be experiencing a representation of tinnitus similar to patients with conductive 51 pathology. Although the subject's matches fall into the cate- gory of those with conductive pathology, the results for the right ear were25 Hz from the upper limit of the category and those for the left ear were 100 Hz from the upper limits. Since this frequency range also overlaps with the frequencies of the sensorineural category, site of salicylic action can- not be drawn from pitch match results. Central Testing Central auditory test results did not appear to demOn— .strate lesion to the central auditory mechanism by salicylates. Under the extreme condition of 60% time compression , the sub- ject showed performance consistent with normative data (Beasley, Schwimmer, and Rintelmann, 1972). The reduction in scores was minimal and within normal limits.» Filtered speech results of this subject compared to the normative data collected in this study did not evidence involve- ment of the central auditory system. Although the findings obtained here were not commesurate with those found by Lynn and Gilroy (1972), Williford (1967) noted that filter character— istics can make a large difference in the results obtained. He cautioned that if the clinician chooses to use filtered speech as a part of the test battery, collection of normative data for the individual tape of filtered speech must be made 52 before application in a test situation. Williford also re- ported that when speech (Northwestern University Auditory ‘Test Number Six) was filtered using a cut-off frequency of 510 Hz and a rejection rate of 30 dB per octave at approx- imately 45 dB SL SRT, normal hearing individuals without temporal lobe disorder score 18.9% correct. His results are consistent with those found in this investigation. The Staggered Spondaic Word (SSW) test and the Simultan- eous Dichotic Consonant-Vowel test were also indicative of normal auditory functioning at the cortical level. The total SSW error was minimal. And, though the subject did not exhibit any tendency for cortical dominance, this is not uncommon. The results of the central test battery suggest that auditory pathology on the cortical level due to salicylate intoxication did not exist in this subject. However, these results must be interpreted cautiously. Other tests of central auditory functioning may yield additional information regarding the effects of salicylates on the higher centers of the auditory system. The tests in this battery evaluated temporal lobe function. Additional tests evaluating brain stem function may indicate some interaction at that level. 53 CONCLUSIONS Data analysis regarding the pitch match was quantitative in nature. The subject matched her tinnitus to a frequency range compatable with individuals with middle ear pathology. Hewever, these frequencies were also reported by Graham and NeWby (1962) for patients with sensorineural lesion. Since the findings of a single subject were to be considered, determination of conductive or sensorineural category could not be made on the basis of pitch match. Brief tone audiometry suggested cochlear site of lesion. Tone decay and acoustic reflex decay results did not reveal abnormal decay of acoustic stimuli. The SISI tested at high sensation levels (Thompson, 1963) also was not indicative of retrocochlear site of lesion. In summary, the results obtained from brief tone audi- ometry appear to confirm Waltner's (1955) hypothesis that the transient hearing loss in this subject may be the effect of an increase in pressure within the cochlea or the effect of enzyme inhibition (Myers and Bernstein, 1965). Therefore this may be considered to be a problem of inner ear cOnduction due to either enzymatic changes or pressure build up in the codhlea. Histopathological studies have not demonstrated consis- tent changes in cochlear or retrocoChlear structures. Audio— metric findings suggest that there is pathology in the inner 54 ear which impedes the efficient transmission of acoustic stimuli.- The tinnitus and transient hearing loss seem to be the result of breakdown in intralabyrinthine fluid transport. The conclusions from this study must be interpreted with caution. This was a single case study, therefore appli- cation to a larger population may be erroneous. However, possible sensitivity of brief tone audiometry should be inves— tigated further. Support for the aforementioned hypotheses can now be seen with audiometric data. IMPLICATIONS FOR FUTURE RESEARCH From this study, two implications for additional re- search can be made. These suggestions are: 1) further examination of the effects of salicylates on the auditory system should be conducted with the test battery used in this study and a larger popu— lation. ' 2) additional study on the effectiveness of brief tone audiometry as an effective determiner of subclinical and/or slight cochlear lesions. ' APPENDICES APPENDIX A CASE HISTORY AUDIOLOGY ADULT HISTORY NAME NR BIRTHDATE 12/26/35' AGE_, 39 OCCUPATION Claims Worker Do you suspect that you have a hearing loss? Yes ' When did you notice the hearing loss? After return from the hospital for treatment for rheumatoid arthritis. Did your spouse (family) notice the loss before that time? No What do you think caused the hearing loss? Aspirin Has the hearing loss Changed since its onset? Yes If so, how? As the aspirin was decreased the hearing, loss lessened. Have you ever worked in a noisy place? No. Did you have to shout to be heard by a person less than three feet away? No. How often did you wear ear protectors? -——- How many years did you work there? ----- Have you ever used guns? No. Snowmobiles? No. Noisy power equipment? No. Describe the present hearing problem (without a hearing aid): Which ear has the hearing loss? Both Does the hearing loss fluctuate(change) from day to day? No. Do you have difficulties hearing the telephone from another room? Yes. Which ear do you use with the tele— phone? Left. Have you always used this ear for the telephone? Left. Have you always used this ear for the telephone? Yes. When did you change and why? ------ . , Do you have to have the speaker talk loudly? No. Do you_have difficulties hearing the doorbell from another room? ‘No bell. If in the same room? ----------- . Is the speech of your family Clear to you? Yes. Is the speech of others clear to you in a noisy room?No. DOes your hearing loss interfere with your work? No ~Does your spouse (family) think you ignore or misunder- stand them? No. , Describe the noises in your ear: Like appond with crickets creaking at night but no frogs. Are the noises constant or intermittent? Mostly there. Which ear? Both. When are they most noticeable? First arising and after taking aspirin What do you do in resonse to loud sounds? Jump. Have you ever tried a hearing aid? No. What kind? ----- How long? ------ During what activites did you use the aid? --------- What problems did you have in using the aid? Page 2 Do you watch people's lips in order to understand their speech? N0. 4. Did you ever take lipreading lessons? No Have you ever had a hearing test before? Where? Yes, last year -- State Health Screening test. Have you ever had a medical evaluation of the hearing problem? Where? When? By whom? No. What other medical problems do you have?Rheumatoid arthritis. For how long? Since May, 1975.‘ Do you get dizzy? Yes. How long does it last? Seconds. Do you feel lightheaded? Or, do you feel that you or the room is spinning? Lightheaded. How often do you get dizzy? Not very often. Do you have some warning (aura) about an impending dizzy spell? No. What causes the dizziness? Do not know. What do you do to stop the dizzy spell? Nothing. Do you have any numbness in your face? No. Which side? ------ At what age? ----- Do you have any difficulty chewing or swallowing? No Has your voice changed in any way? No. - -Do you take aspiring daily? Yes. How many do you take each day? 19 How often do you take aspirin each day? Four times. What other medications do you take? Gold shots. How often? Once each week. For how long? ---------- Have you ever taken any of the following drugs: Kanamycin No. , For how long? ---------- Quinine No. For how long? __________ Streptomycin No. For how long? —————————— Dihydrostreptomycin No For how long? ---------- . ,Have you ever been hit on the head and knocked out? No. Which side? ——————— At what age? ------- What happened?--—- Did you notice any difficulties with your hearing after the measles?No. The mumps? No. Scarlet fever? No. Or, chicken pox? No Who else in your family has a hearing problem? No one. What is -the believed cause of the hearing loss? —————————————— What serious illnesses have you had in the past? None Do you have any difficulties in fine hand coordination? ----- Can you see well enough to read a newspaper? Yes. Have you ever had earaches? Yes. At what age? 30's. Were they medically treated? ----- Did you ever have a tonsilloaden- oidectomy? -Yes. Have you every had surgery on your ears? No. When? ---- For what reason? ~——- . Who is your physician? Dr. R.S. (Rheumatoligist): Dr. G.P and Dr. D.L. (Family Doctors) Page 3 ADDITIONAL COMMENTS ------------------------------------------- I did not notice any hearing loss until I returned from the hospital from being treated for rheumatoid arthritis. I was taking 20 aspirin a day and the first thing I noticed was I could not hear the phone when I was in another room. When I was in the same room with the phone the ring had a funny tone. I now can hear the phone, buy my hearing is still affected. Sometimes I cannot hear a person that is 5' to 10' away. APPENDIX B PITCH MATCH I ANSWER SHEET ANSWER SHEET PRESENTATION HIGHER LOWER EQUAL 10 ll APPENDIX C, D, and E NORTHWESTERN AUDITORY TEST NUMBER SIX FORMS A, B, AND D N.U. Auditory TGSt #6 FORM A File no. Patient Audiometer Audiologist Date Ear Ear Bar Bar Signal dB HL Signal dB HL Signal dB HL Signal dB EL Masking dB HL Masking dB HL Masking dB HL- Masking dB HI. LIST I LIST II LIST III LIST IV laud pick base pass boat room mess doll pool nice cause back nag Said mop red limb fail good wash shout south luck sour sub white walk bone vine keep youth get dime dead pain wheat goose loaf date thumb whip dab pearl sail tough numb search yearn puff juice ditch wife keen chief talk such death merge M ring neat sell wag germ peg take rain life mob fall witch team gas raise soap M __ lid check third young pole join gap ton road lease fat keg __ shall long met calm late (light) chain jar tool check 1:111 door pike beg hole love mill gun lean sure hush jug - tape knock shack “ sheep tire choice read (read) five dip - hash rot rush I rose 101) hate rat came raid live void fit hurl book wire make moon voice half vote page gaze note __ judge yes pad when food reach thought name ripe king bought thin have home turn tell rough I rag chair bar kick which lore mouse lose week 1 bite hire near 8126 haze_ cab perch node Irmdzcchw hit shirt been learn chat bath tip shawl phone time chaIk __ deep soup hall jail gin _ dodge # mood burn goal ' 86126 dog_ kite far +_ cool should _g correct % correct Z correct % correct N.U. Auditory Test #6 FORM.B » . Pile no. Patient Audiometer Audiologist Date Ear _j_ Ear Bar Bar _~ _1 'SIng' dB HL Signal as m. Signal as m. Signal :18 HI. Masking dB HL ‘Masking. dB HL ‘Masking dB HL ‘Msskin dB HL LIST I LIST II _I_.ISI' III LIST IV' burn live I“ shecp__g rose lot voice cause dog; ~ sub ton rat time home learn ._1_ bar such dime 1 match mouse g, have which chair g“_ talk mob keen g“__ deepg hire ,__ bone ,_ yes ., pike search sail A__ boat room ___ luck rough sure L; read (reed) cab dip hurl calm7_ rush join_g 4‘_ door book five check ,__ kite dab team wheat ~_‘ sell . loaf ‘__ pearl thumb neg, (A goal soup near take shack half lease fall far “_ chat yearn ‘week __, witCh ' road kick ‘4_ death ,__. rot. pole get love pick phone lose tough fail life kill !_ gap 4_*_ said pain g‘_ fit moon ~ wag L base judge _ choice haze mop should _#_ king_ white mess pass size hush germ back pool dead thin hell 'vinefl_ g__ pad name bath g_ chalk ,1 mill_, g“, ditch ___ tire __ laud ,__ merge tell peg ,_ goose juice_u, cool perch shout keg seizeWI' chain ‘_ fat gin dodge make puff nice youth long, jar numb hit wash reach chief latejlight) food rag gsze__ jug, mood mode young wire nest tip keep walk ___‘ tape page tool g__ date _g_, ripe raid soap ,‘_ when hole raise __ __ hate ring gas *_ been turn_g check came hash rain note__g vote ___ limb shawl gun lean I third _g bought beg red _g“ jail___ thought void doll knock __ bite shall shirt whip lowerglore) lid sour met south good___ 'wife 1 correct 2 correct '—"% correct 1 correct Z correct Z correct N.U. Auditory Test # FORM D - Patient Audiometer Audiologist Ear Ear ‘ Ear Signal dB HL Signal dB HL Signal dB HL Masking dB HL Masking dB HL Masking dB HL LIST I LIST II LIST III laud loaf germ knock chair talk page goal walk mode shack ditch week far mop hash ___ ton hire yes witch youth third rot pain Whip dab gun love pick dodge lot deep sheep met match mouse limb fail check sell ' said bar door wag phone goose pike beg sub haze mess fat white life cite hush five boat dead seize choice gaze soup chalk live pole hurl keg cab puff calm shall 'reach turn chat raid lore good nag thought note pool tool hit shout rain when tip keep luck size chief tell keen bite jug jail nice pearl sure room base tough book team burn numb wire dime pad date jar bought road rag south cool death juice search bean read (reed) late (light) take merge void home hate rush raise learn rat vine soap thin which young half gap voice name king mill lid moon gin ring fall shawl cause Z correct File No. Date Ear Signal dB HL Masking dB HL LIST IV food lease hall rose doll kill join dip red came hole wash sail mob ripe bone such check wheat should judge gas bath yearn time wife thumb have neat get lose tape make tire near chain shirt long rough fit kick mood lean dog P98 sour pass vote perch back Z correct APPENDIX F RAW NORMATIVE DATA NORMATIVE DATA —- FILTERED SPEECH FORM A FORM B SUBJECT RIGHT EAR LEFT EAR DIFF. SUBJECT RIGHT EAR LEFT EAR DIFF 1 18% 30% 12% 1 . 18% 16% 2% 2 26 32 -6 2 12 16 4 ~ T 3 18 22 4 3 16 20 4 I 4 14 20 6 4 s 16 s ‘ 5 2o 14 6 5 10 12 2 1 APPENDIX G BRIEF TONE TRACINGS ISO 1964 HEARING THRESHOLD LEVEL IN DECIBELS3 BIGH T EAR 500 msec 200 msec 20m ec lcontinuous O 1000 Hz J 10.} ‘ ‘ id x 1" l I .h ‘ _ y x y p v . v " IV V "V 20 1 500 msec 200 msec 20 msec continuous O 2000 Hz 10 - ' I 20 V Y ‘h Apt. d‘fl . I I _ v , I v v n n x 30 ’ SOOmsec ZOOmsec ZOmsec continuous 1 minute _.§ ISO 1964 HEARING THRESHOLD LEVEL IN DECIBELS= LEFI EAR O SOO.Hz ZEAA AAA/V j A 30 ‘V V' AZ M N\A SOOmsec 20 msec V habll‘lsecv V A n inu us IV V IV V 01000 Hz 2; A l I 500 msec 200msec 20mlsevcY c ntinuous I V I _O 2000 Hz 10 20 A / /A A AW 30 L SOOms c 2 Omsec O S C co tnpuo s 4—1minute _,I LIST OF REFERENCE S LIST OF REFERENCES American National Standards Institute, American National Standard Specifications for Audiometers, ANSI 83.6 1969. New York (1970) Anderson, H., Barr, B., and Wedenberg, E.,Early diagnosis of eighth nerve tumors by acoustic reflex tests, Acta Otolar. Suppl,, 263,232-237 (1970). ANON, Drug induced deafness, J. Amer. Med. Assoc., 244, 515- 516 (1963). Ballantyne, J., Iatrogenic deafness, J. Laryn. Otol., 84,. 967-1000 (1970). Ballantyne, J., Ototoxicity: a clinical review, Audiology, 12, 325-336 (1973). Beasley, D.S., Schwimmer, S., and Rintelmann, W.F., Intelligi- bility of time compressed CNC monosyllables, J. Speech Hearing Res,L 15, 340-349 (1972). Berlin, C.L., Lowe, S.S., Thompson, C., and Cullen,J.K., Jr., The construction and perception of simultaneous messages, Asha, 10, 397 (1968). - Bernstein, J.M., and Weiss, A.D., Further observations on salicylate ototoxicity, J. Laryn., 81, 915-925 (1967).' Carhart, R., Clinical determination of abnormal auditory adaptation, Archs Otolar., 65, 32-39 (1957). Carhart, R. and Jerger, J., Perferred method for clinical determination of pure tone thresholds, J. Speech Hearipg Res., 24, 330—345 (1959). Covellf W.F., A cytologic study of the effects of drugs on the cochlea, Archs Otolar., 23, 633-641 (1936). Davis, H. and Kranz, F.W., The international standard reference zero for pure tone audiometers and its relation to the evaluation of impairment of hearing, J. Speech Hearing T335., 7, 7-16 '(1964) De Moura, L.F. and Hayden, R.C., Salicylate ototoxicity: a human temporal bone report, Archs Otolar., 87, 368-372 Djupesland, G., Grdnas, H.E., and Saxegaard, E.F., Hearing and middle ear function in patients with inflammatory rheumatoid diseases, Scan. J. Rheum., 2, 53—56 (1973). Fable—Hansen, J., in Waltner, J.G., Effect of salicylates on the ear, Ann. Otol., 64, 617 (1955) Garner, W.R., The effective frequency spectrum on temporal integration of energy in the ear, J. acoust. Soc. Amer., 19 (1947). Gold, A. and Wilpizeski, G., Studies in auditory adaptation: III some effects of sodium salicylates on evoked auditory potentials in cats, Laryngoscope, 76, 674-685 (1966). Goodwill, S.J., Lord, I.J., and Knill Jones, R.P., Hearing in rheumatoid arthritics: a clinical and audiometric survey Ann. Rheum., 31, 170-173 (1972). Graham, J.T. and Newby, H.A., Acoutical characteristics of tinn- itus, Archs Otolar., 75, 162—167 (1962). Harris, J.D., Haines, H.L., and Meyers, C.K., Brief tone audio— metry, Archs Otolar., 67 (1958). Heyworth, T. and Liyange, S.P., A pilot survey of hearing loss in patients with rheumatoid arthritis, Scan. J. Rheum.; 1, 81-83 (1972). Jarvis,.J.Fl, A case of unilateral permanent deafness following acetysalicylic acid, J. Lar. Otol., 80, 318-320 (1965). Jerger, J., Bekesy audiometry in analysis of auditory disorder, J. Speech Hearing Res., 3, 275-287 (1960). Jerger, J., Shedd, J., and Harford, E., On the detection of extremely small changes in sound intensity, Archs Otolar., 67, 200-211 (1959) Kapur Y.P., Ototoxicity of acetysalicylate acid, Archs Otolar., 81, 134-138 (1965). Katz, J., Basil, R.A., and Smith, J.M., A staggered Spondaic word test for detecting central auditory lesions, Ann. Otol., 72, 908-917 (1963). Kodman, F., Cull, O.A., and Lawson, T.O., Reversible sensori- neural deafness, Laryngoscope, 70, 1273-1283 (1960). Krzanowski, J.J. and Matschinsky, F.M., A phosphocreatine gradient opposite to that of glycogin in the Organ of Corti and the effect of salicylate on adenosine tri- phosphate and p-creatine in cochlear structures,:l; Histochem. Cytochem., 19 321—323 (1971). Laff, H.I., Deafness caused by ototoxic drugs, Rocky Mtn. Med. Jo! 1, 48"50 (1960) o Lee, P., Ahola, S.J., Grennan, D., Brooks, P., and Buchanan, W., Observations on drug prescribing in rheumatoid arthritis, British Med. J., 1 424-426 (1960). 'Lindt, W., in DeMOura L.F. and Hayden, R.C., Salicylate Ototoxicity: a human temporal bone report, Archs OtolarL 87, 368 (1968). Lynn, G.E. and Gilroy, J., Neuro-audiologic abnormalities in patients with temporal lobe tumore, J. Neurol. Sci., 17, 167-184 (1972). McCabe, P. and Dey, F., The effect of aspirin upon auditory sensitivity, Ann. Otol., 74, 312-324 (1965). McPherson, D.L. and Miller, J.M., Choline salicylate, Archs Otolar.L 99, 304-308 (1974). Mosher, H.P., Does animal experimentation show similar changes in the ear of the mother and fetus after ingestion of quinine by the mother? Laryngoscgpe, 48, 361-395 (1938). Mongan, E., Kelly, P. Nies, K., Porter, W.W., and Paulus, H.E., Tinnitus as an indication of theraputic serum salicylate levels, J. Amer. Med. Assoc., 226 142-145 (1973). Meyers, E.N. and Bernstein, J.M.,' Salicylate ototoxicity: a clinical and experimental study, Archs Otolar., 82, 483-493 (1965). ' Myers, E.N., Bernstein, J.M., and Fostiropolous, G., Salicylate ototoxicity: a clinical study, g§w_Epgl. J. MedéJ 273,587-590 (1965). Nodar, R.H. and Graham, J.T., An investigation of frequency characteristics of tinnitus associated with Meniere's disease, Archs Otolar., 82, 28-31 (1965). Olsen, W. and Carhart, R., Brief tone audiometry, J. Acoust. Soc. Amer., 40, 591-599 (1966). Pedersen, C.B., Brief tone audiometry in persons with salicy- lates, Audiology, 13, 311-319 (1974). Perlman, L.V., Salicylate intoxication from skin application, New Engl. J. Med.,274, 164 (1966). Rosenberg, P.E., The test battery approach, Handbook of Clinical Audiology. Baltimore: The Williams/Wilkins Company (1972). Sanders, J.W., Josey, A.F., and Glascock, M.E., Audiologic evaluation in cochlear and eight nerve disorders, Archs Otolar.,lOO, 283-285 (1974). Sheffield, P.A. and Turner, J.S., Ototoxic drugs: a review of clinical aspects, histopathologic changes, and mechanisms of action, S2, Med. J., ‘64,359-363 (1971). Silverstein, H. Bernstein, J.M., and Davis, D.G., Salicylate ototoxicity: a biochemical and electrophysiological study, Ann. Otol., 76, 119-128 (1967). Smith, M.J.H., Metabolic effects of salicylates, Salicylate, International Symposium. Little, Brown, and Company 11963). Stebbins, W.C., Miller, J.M., Johnson, L.G., and Hawkins, J.E., Ototoxic hearing loss and cochlear pathology in the monkey, Ann. Otol., 78, 1007-1025 (1969). Thalman, R., Miyoshi, T., Kusokari, J., and Thalman, 1., Quantitative approaches to the ototoxicity problem, Audiology, 12; 364-382 (1973). Thompson, G.A., A modified SISI technique for selected cases with suspected acoustic neurinoma, J. Speech Hearing Dis., 28, 299-302 (1963). Tillman, T. and Carhart, R., An expanded test for speech discrimination utilizing CNC monosyllabic words (North- western University Auditory Test No. 6). Technical Report, SAM-TR-66-55, USAF School of Aerospace Medicine, Aerospace Medical Division (AFSC), Brooks Air Force Base, Texas (1966). Waltner, J.G., Effects of salicylates on the ear, Ann. Otol., 64,617-622 (1955). Williford, J.A., Audiological evaluation of central auditory ' disorders, I., Maico Audiological Library Series,6 _Report 1 (1967). Wittmaak, K., in DeMoura, L.F. and Hayden,_R.C., Salicylate ototoxicity: a human temporal bone report, Archs Otolar., 87,368 (1968). Wright, H.R., Clinical measurement of temporal auditory summation, J. Speech Hearing Res., 11, 109-127 (1968). MICHIGAN STATE UNIV. LIBRARIES IIIBIIIIII lIllllIlIlllllIllllIIlll llllIlllllII 931 07 665 2 3 30