Ann Otol Rhinol LaryngoI 100:1991
ZINC IN THE MANAGEMENT OF TINNITUS PLACEBO-CONTROLLED TRIAL PETER B. P AASKE,
MD
CHRISTIAN BRAHE PEDERSEN,
GUNNAR KJEMS
MD
IAN LAW KUNG SAM AARHus, DENMARK
To assess anypossible beneficial effect from zincontinnitus weperformed a placebo-controlled, randomized, double-blind investigation. Forty-eight patients with tinnitus wererandomized to eitherplacebo or the administration ofzincsulfate assustained-release tablets of 22 mg Zn" (Zinldet). Thetablets wereadministered threetimes daily for 8 weeks. Every week thepatients statedthe severity oftinnitus on a number scale from 0 to 10. Thelevels ofzincand albumin in serum weredetermined bothbefore and aftertreatment. Of 48 patients with tinnitus, hypozincemia wasfound in onlyone patient. The zinclevel increased significantly in the patients treatedwith zinc. We could notdemonstrate anybeneficial effect from zincontinnitus. Oneoftheessential reasons forthisfinding could be that thezinc levels in serum werein the normal range previous to treatment. KEY WORDS - tinnitus, zinc. INTRODUCTION
soundproof box. The thresholds of air conduction and bone conduction including the speech reception threshold were measured in decibels hearing level. The speech discrimination loss was measured in percent. The threshold of the stapedial reflex was measured by contralateral stimulation. The frequency of tinnitus was measured in the same way.
The importance of zinc for the human organism was demonstrated in 1961 by Prasad et al.! Investigations on guinea pigs have shown a high content of zinc in the inner ear. 2 This finding has given occasion to some speculation on the role of zinc in inner ear function. A correlation between hypozincemia and tinnitus has been reported." In an uncontrolled trial by Gersdorff et a14 zinc was found to reduce tinnitus. Shambaugh! found an improvement in tinnitus in 25% of patients with tinnitus and hypozincemia. The purpose of our investigation, arranged as a double-blind, randomized, placebo-controlled trial, was to study any possible beneficial effect from zinc on tinnitus.
To evaluate the tinnitus and possibly contemporary hearing loss or vertigo, the patients were examined by brain stem auditory evoked potentials, calorimetric measurement by the Hallpike method, computed tomography, and ophthalmologic and neurologic tests.
EXAMINATIONS
The test tablets were administered three times daily for 8 weeks. The tablets were randomized and contained either placebo or 100 m-g zinc sulfate (22 mg Zn'") as sustained-release tablets (Zinklet).
A blood sample (in the morning before eating or drinking) was taken to determine the level of zinc and albumin in serum, as zinc is bound to albumin.
Fifty patients initially participated in the investigation. All 50 previously or currently were admitted to the audiology department, Aarhus University Hospital, because of tinnitus. They all suffered from tinnitus to such a degree that they wanted some form of treatment. Later, 2 patients were excluded because they did not complete the treatment. The material, therefore, consisted of 48 patients: 31 men (65%) and 17 women (350/0). The median and range of age appear in Table 1. For every patient only one ear was assessed in the investigation. In bilateral tinnitus the effect on treatment was assessed in the ear with the worse tinnitus. The duration of tinnitus and any psychosocial inconveniences were noted.
To assess a possible change in the loudness of tinnitus we chose to let the patient's own assessment be the baseline. For that purpose a numeric scale from oto 10 was used. Zero signified no tinnitus and 10 a severe and unbearable tinnitus. The strength of tinnitus was entered on the numeric scale before treatment began. Every week until the treatment ceased the patients used the scale to state the strength of tinnitus for the previous week. TABLE 1. DISTRIBUTION OF PATIENTS ACCORDING TO AGE IN TWO TREATMENT GROUPS Zinc
A typical otologic and audiologic examination was carried out. Pure tone audiometry was performed with a Madsen audiometer (OB 802) in a
Placebo
Number
23
25
Median age Age range
60
48 29-77
33-76
From the Audiological and ENT Department, University Hospital of Aarhus, Aarhus, Denmark. REPRINTS - Peter B. Paaske, MD, ENT Dept, University Hospital of Aarhus, DK-8000 Aarhus C, Denmark.
647
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
Total 48 57 29-77
648
Paaske et al, Zinc in Management oj Tinnitus TABLE 3. ZINC LEVEL IN SERUM BEFORE AND AFTER TREATMENT IN TWO GROUPS
TABLE 2. DIAGNOSIS FROM AUDIOMETRY IN 48 PATIENTS WITH TINNITUS
Cause
No.
Sensorineural hearing loss of unknown cause (2 patients with sudden deafness) Noise-induced hearing loss Noncongenital, hereditary sensorineural hearing loss Sequelae to chronic otitis media Tinnitus without hearing loss Others (presbyacusis, temporal bone fracture, etc)
20
8 6 3 3
8
The effect was assessed at the end of treatment. Every score lesser or greater than before treatment that had persisted for at least a fortnight at the end of treatment was interpreted as an improvement or impairment in tinnitus, respectively. In all other cases the results were assessed as unchanged. After cessation of treatment a new blood sample was taken to measure the level of zinc and albumin in serum. The zinc level was determined in undiluted serum by flame atomic absorption spectrophotometry with use of a matrix-matched (12 % glycerol) standard curve." Normal values of zinc range from 10 to 19 p.mol/L. The Wilcoxon rank sum test and Fisher's exact test were used in the statistical calculations. To analyze any correlation between zinc and albumin in serum the Spearman rank correlation test was applied. A significance level of 5 % was chosen. RESULTS
The duration of tinnitus varied from 3 months to 34 years (median, 5 years). Three of the patients had suffered from tinnitus less than 6 months. In 11 patients (23 0/0) the tinnitus was present in the right ear, in 20 (42 %) in the left ear, and in 16 patients (33 0/0) in both ears. In 1 patient (2 0/0) the tinnitus was described as central. Forty-two patients (88 %) suffered from constant and 6 patients (12 %) from an intermittent tinnitus. Twenty-one patients (44 %) experienced tinnitus as a high-frequency sound, 24 (50 %) experienced it as a low-frequency sound, and 2 (4%) experienced both kinds of sounds. One patient (2 %) experienced
Zinc group Median Range Placebo group Median Range
Before
After
Difference *
13.3 8.0-17.2
15.4 11.3-29.9
2.3 -0.5-16.0
12.5
12.9 10.2-15.3
0.0 -5.3- 2.5
10.5~17. 7
Values are JLl11ollL. "Calculated on basis of individual values.
a pulsating tinnitus. A total of 32 patients (67 0/0) suffered from psychosocial difficulties: 16 patients had difficulty in concentrating, 8 had difficulty in falling asleep, and 19 patients sometimes had difficulty in discriminating speech. From audiometry the diagnoses were made as shown in Table 2. The determinations of the frequency of tinnitus appear in the Figure. The frequency was measured as pure tones in 26 patients and as narrow bands in 21 patients. In one case tinnitus was determined as white noise. The distribution of the patients in the two different treatment groups appears in Table 1. No significant difference in age between the two groups was found. The zinc levels appear in Table 3. In the zinctreated group the zinc level increased significantly (p< .01), whereas the zinc level was unchanged in the placebo group. The albumin levels appear in Table 4. No correlation between zinc and albumin in serum was found; hence, a rise in zinc could not be attributed to an increase in albumin. Only one zinc value was below the normal range; this was in a patient before treatment. Four zinc values were above the normal range, all among patients who had received zinc.
10 -
In both treatment groups two patients had an improvement in tinnitus. Two patients in the zinctreated group and five patients in the placebo group had a deterioration. All other patients experienced no change in tinnitus. There was no significant difference between the results in the two groups (p = 1). The risk of a type 2 error was 2.1 0/0.
8-
One patient stopped the treatment by herself 6
Number
TABLE 4. ALBUMIN LEVEL IN SERUM BEFORE AND AFTER TREATMENT IN TWO GROUPS
64-
2
-
o
fij I
0,25 0,5
I
",
2
4
8 ?:10 kHz
Frequency of tinnitus (measured in kilohertz) in "47 patients'.
Zinc group Median Range Placebo group Median Range
Before
After
Difference *
38.6 33.1-43.0
36.8 33.2-43.1
-0.85 -4.8-3.1
37.6 31.6-42.2
36.9 29.6-41.5
-0.8 -5.2-2.6
Values are giL. "Calculated on basis of individual values.
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
Paaske et al, Zinc in Management of Tinnitus
weeks after the initiation because of an impairment in an enduring depression. This patient received zinc and is included in the investigation. No side effects that could be attributed to the tablets were noticed. DISCUSSION
Tinnitus is a symptom frequently encountered in diseases of the labyrinth, the eighth cranial nerve, and central communications. No pathophysiologic explanation of the nature of tinnitus is available; this uncertainty is reflected in the many forms of treatment that have been proposed, often with contradictory results." Investigations on animal models indicate that tinnitus is of cochlear origin. 8 One of the theories" is based on the assumption that minor traumata in the organ of Corti or pressure on the eighth cranial nerve might cause spontaneous activity in the cochlea. Normally, this activity is not perceived as sound, but it may be spread to other nerve fibers, resulting in tinnitus. The recommended daily allowance of zinc in adults is 15 mg. 10 The majority of the zinc content in humans is bound to proteins in the tissues. In plasma, zinc is primarily bound to albumin; less than 2 % of zinc in the organism is found free in plasrna.!" The zinc level in serum is not a good parameter, but is the most reliable one for assessing the zinc balance in the organism. 2 The metabolism of zinc in the inner ear is described by Prasad. 11 Some years ago Shambaugh" published a report in which a positive effect of zinc in some patients with severe tinnitus was found. Later, Gersdorff et al" found a connection between tinnitus and a low level of zinc in serum. They found that 68.70/0 of 115 patients with tinnitus had hypozincemia. By
649
the administration of zinc tablets in 4 to 10 times the recommended daily allowance for 3 to 6 months, Shambaugh'> found an improvement in tinnitus in 25 % of patients with tinnitus and hypozincemia. Nobody experienced cessation of tinnitus. The investigation of Gersdorff et al" with the administration of zinc in 27 patients with tinnitus and hypozincemia showed a good improvement in 4 patients (15 0/0) and a lesser improvement in 10 patients (37 %). The trial was not placebo-controlled. One of the difficulties in assessing a possible effect in the treatment of tinnitus is that tinnitus is a subjective phenomenon that only to some extent may be measured." We therefore chose to assess a possible effect of treatment by the patient's own judgment alone. The investigation from Gersdorff et al" was arranged in the same way. Our investigation could not confirm the high incidence of hypozincemia in patients with tinnitus as reported by other authors.s'? Only one patient in our trial presented hypozincemia. That patient received zinc but without any effect on tinnitus. We found an increase in the zinc level in serum in those patients who received the active treatment. However, no effect on tinnitus was found. In the investigation from Gersdorff et al" all the patients presented hypozincemia; this difference might be an essential reason for a result different from ours. However, the report from Gersdorff et al was not a placebo-controlled trial. From our investigation we may conclude that hypozincemia is not a common finding in patients with tinnitus and that the administration of zinc for 8 weeks has no effect on tinnitus.
REFERENCES 1. Prasad AS, Halstead JA, Nadimi M. Syndrome of iron-deficiency, anaemia, hepato-splenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;31:532-3.
7. Goodey RJ. Drugs in treatment of tinnitus. In: Evered D, Lawrenson G, eds. Tinnitus. Ciba Foundation Symposium 85. London, England: Pitman Books, 1981:263-91.
2. Shambaugh GE Jr. Zinc and presbycusis. Am J Oto11985; 6:116-7.
8. Evans EF, Wilson JP, Borerwe TA. Animal models of tinnitus. In: Evered D, Lawrenson G, eds. Tinnitus. Ciba Foundation Symposium85. London, England: Pitman Books, 1981:108-38.
3. Gersdorff M, Robillard T, Steni F, Declaye X, van der Bemden S. A clinical correlation between hypozincemia and tinnitus. Arch Otorhinolaryngol 1987;244:190-3. 4. Gersdorff M, Robillard T, Steni F, Declaye X, van der Bemden S. Epreuve surcharge au sulfate de zinc chez des patients souffrant d'aoouphenes assoclees a une hypozincemie. Acta Otorhinolaryngol Belg 1987;41:498-505. 5. Shambaugh GE. How essential is zinc for sensory functions? Newsletter No.9. Chicago, Ill: Shambaugh Medical Research Institute, 1984. 6. Pekarek RS, Beisel WR, Bartelloni PJ, Bostian KA. Determination of serum zinc concentrations in normal adult subjects by atomic absorption spectrophotometry. Am J CUn PathoI1972;57: 506-10.
9. M~ller AB. Pathophysiology of tinnitus. Ann Otol Rhinol LaryngoI1984;93:39-44. 10. Wahid MA, Fathi SAH, Aboul-Khair MR. Zinc in human health and disease. Ric Clin Lab 1988;18:9-16. 11. Prasad AS. Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983;7: 197-208. 12. Shambaugh GE Jr. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J OtoI1986;7:476-7. 13. Feldmann H. Homolateral and contralateral masking of tinnitus by noise-bands and by pure tones. Audiology 1971;10: 138-44.
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
ZINC IN THE MANAGEMENT OF TINNITUS PLACEBO-CONTROLLED TRIAL PETER B. P AASKE,
MD
CHRISTIAN BRAHE PEDERSEN,
GUNNAR KJEMS
MD
IAN LAW KUNG SAM AARHus, DENMARK
To assess anypossible beneficial effect from zincontinnitus weperformed a placebo-controlled, randomized, double-blind investigation. Forty-eight patients with tinnitus wererandomized to eitherplacebo or the administration ofzincsulfate assustained-release tablets of 22 mg Zn" (Zinldet). Thetablets wereadministered threetimes daily for 8 weeks. Every week thepatients statedthe severity oftinnitus on a number scale from 0 to 10. Thelevels ofzincand albumin in serum weredetermined bothbefore and aftertreatment. Of 48 patients with tinnitus, hypozincemia wasfound in onlyone patient. The zinclevel increased significantly in the patients treatedwith zinc. We could notdemonstrate anybeneficial effect from zincontinnitus. Oneoftheessential reasons forthisfinding could be that thezinc levels in serum werein the normal range previous to treatment. KEY WORDS - tinnitus, zinc. INTRODUCTION
soundproof box. The thresholds of air conduction and bone conduction including the speech reception threshold were measured in decibels hearing level. The speech discrimination loss was measured in percent. The threshold of the stapedial reflex was measured by contralateral stimulation. The frequency of tinnitus was measured in the same way.
The importance of zinc for the human organism was demonstrated in 1961 by Prasad et al.! Investigations on guinea pigs have shown a high content of zinc in the inner ear. 2 This finding has given occasion to some speculation on the role of zinc in inner ear function. A correlation between hypozincemia and tinnitus has been reported." In an uncontrolled trial by Gersdorff et a14 zinc was found to reduce tinnitus. Shambaugh! found an improvement in tinnitus in 25% of patients with tinnitus and hypozincemia. The purpose of our investigation, arranged as a double-blind, randomized, placebo-controlled trial, was to study any possible beneficial effect from zinc on tinnitus.
To evaluate the tinnitus and possibly contemporary hearing loss or vertigo, the patients were examined by brain stem auditory evoked potentials, calorimetric measurement by the Hallpike method, computed tomography, and ophthalmologic and neurologic tests.
EXAMINATIONS
The test tablets were administered three times daily for 8 weeks. The tablets were randomized and contained either placebo or 100 m-g zinc sulfate (22 mg Zn'") as sustained-release tablets (Zinklet).
A blood sample (in the morning before eating or drinking) was taken to determine the level of zinc and albumin in serum, as zinc is bound to albumin.
Fifty patients initially participated in the investigation. All 50 previously or currently were admitted to the audiology department, Aarhus University Hospital, because of tinnitus. They all suffered from tinnitus to such a degree that they wanted some form of treatment. Later, 2 patients were excluded because they did not complete the treatment. The material, therefore, consisted of 48 patients: 31 men (65%) and 17 women (350/0). The median and range of age appear in Table 1. For every patient only one ear was assessed in the investigation. In bilateral tinnitus the effect on treatment was assessed in the ear with the worse tinnitus. The duration of tinnitus and any psychosocial inconveniences were noted.
To assess a possible change in the loudness of tinnitus we chose to let the patient's own assessment be the baseline. For that purpose a numeric scale from oto 10 was used. Zero signified no tinnitus and 10 a severe and unbearable tinnitus. The strength of tinnitus was entered on the numeric scale before treatment began. Every week until the treatment ceased the patients used the scale to state the strength of tinnitus for the previous week. TABLE 1. DISTRIBUTION OF PATIENTS ACCORDING TO AGE IN TWO TREATMENT GROUPS Zinc
A typical otologic and audiologic examination was carried out. Pure tone audiometry was performed with a Madsen audiometer (OB 802) in a
Placebo
Number
23
25
Median age Age range
60
48 29-77
33-76
From the Audiological and ENT Department, University Hospital of Aarhus, Aarhus, Denmark. REPRINTS - Peter B. Paaske, MD, ENT Dept, University Hospital of Aarhus, DK-8000 Aarhus C, Denmark.
647
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
Total 48 57 29-77
648
Paaske et al, Zinc in Management oj Tinnitus TABLE 3. ZINC LEVEL IN SERUM BEFORE AND AFTER TREATMENT IN TWO GROUPS
TABLE 2. DIAGNOSIS FROM AUDIOMETRY IN 48 PATIENTS WITH TINNITUS
Cause
No.
Sensorineural hearing loss of unknown cause (2 patients with sudden deafness) Noise-induced hearing loss Noncongenital, hereditary sensorineural hearing loss Sequelae to chronic otitis media Tinnitus without hearing loss Others (presbyacusis, temporal bone fracture, etc)
20
8 6 3 3
8
The effect was assessed at the end of treatment. Every score lesser or greater than before treatment that had persisted for at least a fortnight at the end of treatment was interpreted as an improvement or impairment in tinnitus, respectively. In all other cases the results were assessed as unchanged. After cessation of treatment a new blood sample was taken to measure the level of zinc and albumin in serum. The zinc level was determined in undiluted serum by flame atomic absorption spectrophotometry with use of a matrix-matched (12 % glycerol) standard curve." Normal values of zinc range from 10 to 19 p.mol/L. The Wilcoxon rank sum test and Fisher's exact test were used in the statistical calculations. To analyze any correlation between zinc and albumin in serum the Spearman rank correlation test was applied. A significance level of 5 % was chosen. RESULTS
The duration of tinnitus varied from 3 months to 34 years (median, 5 years). Three of the patients had suffered from tinnitus less than 6 months. In 11 patients (23 0/0) the tinnitus was present in the right ear, in 20 (42 %) in the left ear, and in 16 patients (33 0/0) in both ears. In 1 patient (2 0/0) the tinnitus was described as central. Forty-two patients (88 %) suffered from constant and 6 patients (12 %) from an intermittent tinnitus. Twenty-one patients (44 %) experienced tinnitus as a high-frequency sound, 24 (50 %) experienced it as a low-frequency sound, and 2 (4%) experienced both kinds of sounds. One patient (2 %) experienced
Zinc group Median Range Placebo group Median Range
Before
After
Difference *
13.3 8.0-17.2
15.4 11.3-29.9
2.3 -0.5-16.0
12.5
12.9 10.2-15.3
0.0 -5.3- 2.5
10.5~17. 7
Values are JLl11ollL. "Calculated on basis of individual values.
a pulsating tinnitus. A total of 32 patients (67 0/0) suffered from psychosocial difficulties: 16 patients had difficulty in concentrating, 8 had difficulty in falling asleep, and 19 patients sometimes had difficulty in discriminating speech. From audiometry the diagnoses were made as shown in Table 2. The determinations of the frequency of tinnitus appear in the Figure. The frequency was measured as pure tones in 26 patients and as narrow bands in 21 patients. In one case tinnitus was determined as white noise. The distribution of the patients in the two different treatment groups appears in Table 1. No significant difference in age between the two groups was found. The zinc levels appear in Table 3. In the zinctreated group the zinc level increased significantly (p< .01), whereas the zinc level was unchanged in the placebo group. The albumin levels appear in Table 4. No correlation between zinc and albumin in serum was found; hence, a rise in zinc could not be attributed to an increase in albumin. Only one zinc value was below the normal range; this was in a patient before treatment. Four zinc values were above the normal range, all among patients who had received zinc.
10 -
In both treatment groups two patients had an improvement in tinnitus. Two patients in the zinctreated group and five patients in the placebo group had a deterioration. All other patients experienced no change in tinnitus. There was no significant difference between the results in the two groups (p = 1). The risk of a type 2 error was 2.1 0/0.
8-
One patient stopped the treatment by herself 6
Number
TABLE 4. ALBUMIN LEVEL IN SERUM BEFORE AND AFTER TREATMENT IN TWO GROUPS
64-
2
-
o
fij I
0,25 0,5
I
",
2
4
8 ?:10 kHz
Frequency of tinnitus (measured in kilohertz) in "47 patients'.
Zinc group Median Range Placebo group Median Range
Before
After
Difference *
38.6 33.1-43.0
36.8 33.2-43.1
-0.85 -4.8-3.1
37.6 31.6-42.2
36.9 29.6-41.5
-0.8 -5.2-2.6
Values are giL. "Calculated on basis of individual values.
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
Paaske et al, Zinc in Management of Tinnitus
weeks after the initiation because of an impairment in an enduring depression. This patient received zinc and is included in the investigation. No side effects that could be attributed to the tablets were noticed. DISCUSSION
Tinnitus is a symptom frequently encountered in diseases of the labyrinth, the eighth cranial nerve, and central communications. No pathophysiologic explanation of the nature of tinnitus is available; this uncertainty is reflected in the many forms of treatment that have been proposed, often with contradictory results." Investigations on animal models indicate that tinnitus is of cochlear origin. 8 One of the theories" is based on the assumption that minor traumata in the organ of Corti or pressure on the eighth cranial nerve might cause spontaneous activity in the cochlea. Normally, this activity is not perceived as sound, but it may be spread to other nerve fibers, resulting in tinnitus. The recommended daily allowance of zinc in adults is 15 mg. 10 The majority of the zinc content in humans is bound to proteins in the tissues. In plasma, zinc is primarily bound to albumin; less than 2 % of zinc in the organism is found free in plasrna.!" The zinc level in serum is not a good parameter, but is the most reliable one for assessing the zinc balance in the organism. 2 The metabolism of zinc in the inner ear is described by Prasad. 11 Some years ago Shambaugh" published a report in which a positive effect of zinc in some patients with severe tinnitus was found. Later, Gersdorff et al" found a connection between tinnitus and a low level of zinc in serum. They found that 68.70/0 of 115 patients with tinnitus had hypozincemia. By
649
the administration of zinc tablets in 4 to 10 times the recommended daily allowance for 3 to 6 months, Shambaugh'> found an improvement in tinnitus in 25 % of patients with tinnitus and hypozincemia. Nobody experienced cessation of tinnitus. The investigation of Gersdorff et al" with the administration of zinc in 27 patients with tinnitus and hypozincemia showed a good improvement in 4 patients (15 0/0) and a lesser improvement in 10 patients (37 %). The trial was not placebo-controlled. One of the difficulties in assessing a possible effect in the treatment of tinnitus is that tinnitus is a subjective phenomenon that only to some extent may be measured." We therefore chose to assess a possible effect of treatment by the patient's own judgment alone. The investigation from Gersdorff et al" was arranged in the same way. Our investigation could not confirm the high incidence of hypozincemia in patients with tinnitus as reported by other authors.s'? Only one patient in our trial presented hypozincemia. That patient received zinc but without any effect on tinnitus. We found an increase in the zinc level in serum in those patients who received the active treatment. However, no effect on tinnitus was found. In the investigation from Gersdorff et al" all the patients presented hypozincemia; this difference might be an essential reason for a result different from ours. However, the report from Gersdorff et al was not a placebo-controlled trial. From our investigation we may conclude that hypozincemia is not a common finding in patients with tinnitus and that the administration of zinc for 8 weeks has no effect on tinnitus.
REFERENCES 1. Prasad AS, Halstead JA, Nadimi M. Syndrome of iron-deficiency, anaemia, hepato-splenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;31:532-3.
7. Goodey RJ. Drugs in treatment of tinnitus. In: Evered D, Lawrenson G, eds. Tinnitus. Ciba Foundation Symposium 85. London, England: Pitman Books, 1981:263-91.
2. Shambaugh GE Jr. Zinc and presbycusis. Am J Oto11985; 6:116-7.
8. Evans EF, Wilson JP, Borerwe TA. Animal models of tinnitus. In: Evered D, Lawrenson G, eds. Tinnitus. Ciba Foundation Symposium85. London, England: Pitman Books, 1981:108-38.
3. Gersdorff M, Robillard T, Steni F, Declaye X, van der Bemden S. A clinical correlation between hypozincemia and tinnitus. Arch Otorhinolaryngol 1987;244:190-3. 4. Gersdorff M, Robillard T, Steni F, Declaye X, van der Bemden S. Epreuve surcharge au sulfate de zinc chez des patients souffrant d'aoouphenes assoclees a une hypozincemie. Acta Otorhinolaryngol Belg 1987;41:498-505. 5. Shambaugh GE. How essential is zinc for sensory functions? Newsletter No.9. Chicago, Ill: Shambaugh Medical Research Institute, 1984. 6. Pekarek RS, Beisel WR, Bartelloni PJ, Bostian KA. Determination of serum zinc concentrations in normal adult subjects by atomic absorption spectrophotometry. Am J CUn PathoI1972;57: 506-10.
9. M~ller AB. Pathophysiology of tinnitus. Ann Otol Rhinol LaryngoI1984;93:39-44. 10. Wahid MA, Fathi SAH, Aboul-Khair MR. Zinc in human health and disease. Ric Clin Lab 1988;18:9-16. 11. Prasad AS. Clinical, biochemical and nutritional spectrum of zinc deficiency in human subjects: an update. Nutr Rev 1983;7: 197-208. 12. Shambaugh GE Jr. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J OtoI1986;7:476-7. 13. Feldmann H. Homolateral and contralateral masking of tinnitus by noise-bands and by pure tones. Audiology 1971;10: 138-44.
Downloaded from aor.sagepub.com at Bobst Library, New York University on June 18, 2015
