Comparative study of brainstem evoked response audiometry in diabetic patients and non-diabetic subjects to assess the involvement of central auditory pathway

INTRODUCTION

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, protein and fat metabolism resulting from either defect in insulin action or insulin secretion or both1. It can have long-term effects on the various organs of the body like the eye, kidneys, heart, peripheral vessels and nerves. The metabolic derangement is frequently associated with permanent and irreversible/ functional and structural changes in the cells of the body, vascular system being particularly susceptible, peripheral neuropathy is a frequent complication of the diabetes. Autonomic nervous system involvement and isolated nerve palsies are well known to occur in diabetics. Eber’s papyrus was the first one to mention about diabetes as early as 1500 Banting et al discovery of Insulin was a significant milestone in the history of diabetes. Since then, many dedicated researches have helped us understand this disease better.

Neurophysiological studies in diabetic patients involving the CNS were done using evoked potential and measuring its latencies. Prolonged latencies of these evoked potentials measured using visual evoked potential, somatosensory evoked potential and brain stem auditory evoked potential have been reported often. In this study, BERA/Auditory brainstem response (ABR) of diabetic patients to those of age and gender matched controls were assessed for the involvement of central auditory pathway.

Objective

Objectives of the study were to assess the auditory function and incidence of central auditory pathway involvement in patients with diabetes compared to age and sex matched non diabetic subjects, using ABR/BERA, to compare the absolute latency of wave I, wave III and wave V between the study and control groups, to compare the interpeak latency I to III, III to V and I to V between the groups and to interpret the ABR values based on the duration of diabetes

METHODS

Study design

The study design was of cross-sectional comparative study.

Place of study

The study carried out at government Kilpauk medical college hospital.

Study period

The study conducted from November 2019 to October 2020.

Ethical committee approval:

The ethical committee approval was obtained.

Sample size

The 35 subjects in each group were selected for the study,

Calculated using sample size formula, n=(Za + Zb) 2S 2 / (X1-X2) 2.

Patient with clinical diagnosis of DM fulfilling following criteria were enrolled in the study.

Inclusion criteria

For cases

Patients diagnosed and treated for diabetes at the department of diabetes, government Kilpauk medical college hospital, according to WHO diagnostic criteria and with age between>35 years and <55 years were included in the study.

For controls

Age and sex matched with diabetic subjects from the general OPD and general population, after confirming that fasting and post prandial blood glucose within normal limits according to WHO diagnostic criteria were included.

Exclusion criteria

For both groups

Patients with external or middle ear disease, head injury and ear trauma, history of previous ear surgery, ototoxic drugs intake like aminoglycosides, family history of deafness, chronic exposure in noisy environment, medications that might affect the normal functioning the central nervous system (anti-depressants, anti-psychotics, methyldopa etc.,) and patient with any systemic illness that might affect the central nervous system (uremia, stroke, hepatic encephalopathy, multiple sclerosis, anemia, meningitis). Any history of radiotherapy or chemotherapy were excluded from the study.

For cases

Along with above mentioned exclusions and any patients with acute complications of diabetes like ketoacidosis, hypoglycaemia was excluded.

For controls

Along with above mentioned exclusions and past history of diabetes were excluded.

It is a comparative cross-sectional study. Total of 35 patients with DM belonging to either sex, with age ranging between 35 to 55 years and duration of diabetes ranging more than 1 year were enrolled. Control group with age and sex matched with study group were enrolled. Blood sugar profile and diabetologist opinion obtained. Detailed history taken and clinical examination done to rule out other causes of auditory dysfunction. Patient explained about the study and consent taken. Pure tone audiometry done before hand. BERA was done in all patients, latencies of waves I, III, and V and inter- peak latencies I-III, I-V and III-V were analysed. Mann-Whitney U test and Kruskal Wallis test was applied for statistical analysis. P<0.001 is highly significant, p≥0.05 not significant.

RESULTS

In our study, a statistically significant prolongation was observed in wave III latency at 70, 80 and 90 dBnHL in diabetic group compared to the control group. Similarly, the latency of wave V was significantly delayed in 70, 80 and 90dBnHL in diabetic group as compared to the controls with wave V being highly significant at 70 and 90 dB. There was no significant interaural latency difference. In diabetic patients, latencies of waves I, III, and V and inter- peak latencies IIII, I-V and III-V were significantly delayed. No relation was found with the duration of DM. In our study, we concluded that diabetes and BERA abnormalities are significantly associated which has also been substantiated by numerous preceding studies as in Donald et al in their study conducted ABR tests on 20 IDDM patients and found that the latency of wave III, wave V, interwave latency I-III and I-V were significantly delayed.² For wave III the delay was by 0.30 ms (p<0.05- significant) and the delay in latency of wave V was by 0.45 ms (p<0.001- highly significant) on 70, 80, and 90 dB respectively. Likewise, the interpeak/interwave latency of wave I-III and the interpeak latency wave I-V was delayed by 0.24 ms (p<0.01) and 0.35 ms (p<0.05) respectively.

The mean age of the study participants was 46.9±5.1 years.

*Mann-Whitney U test was applied. P<0.05 was considered significant p≤0.001 is the highly significant, p≥0.05 not significant.

*Mann-Whitney U test was applied. P<0.05 was considered significant p≤0.001 is the highly significant, p≥0.05 not significant.

*Mann-Whitney U test was applied. P<0.05 was considered significant p≤0.001 is highly significant, p≥0.05 not significant.

The mean duration of diabetes among the study participants was 8.1±3.5 years. Kruskal Wallis test was applied. P<0.05 was considered significant p≤0.001 is highly significant.

The absolute latency of wave III and wave V was significant across all 70-, 80- and 90-dB stimuli with absolute latency of wave V being highly significant at 70 and 90 dB in the diabetic group compared to the control group. The interpeak/ interwave latency of I-III was significant at 70 and 90 dB. The interpeak/ interwave latency of I-V, III-V was highly significant across all the 70-, 80- and 90-dB stimuli compared to the control group.

DISCUSSION

The hearing difficulties associated with diabetic patients are of gradual onset and are bilateral, symmetric and progressive high frequency sensorineural hearing loss. Cochlear, Retro cochlear or combined cochlear and retro cochlear involvement of acoustic nerve are considered as the probable cause for this hearing difficulties encountered in patients with diabetes. Though the pathogenesis of hearing loss in these patients has not been fully clarified, it involves a multifactorial process.

Use of an objective, reliable and non-invasive method like ABR/ BERA can detect even the subclinical involvement of the auditory pathway, by recording the electrical potentials occurring along the auditory pathway. As a result, ABR/BERA can be used as a reliable, non-invasive tool for diagnosing lesions starting vestibulocochlear nerve to the auditory areas in brain. Delay in the latency of ABR waves were reported in various reports from the time when the ABR was started as a tool for diagnostic purpose. But the earliest to use BERA and to identify the delays in latency in the wave associated with auditory nerve in DM patients was done by Donald et al.²

Fedelle et al also reported the prolonged latency of all the components of ABR.³ They studied 30 normo acoustic IDDM subjects between 15 and 41 years and compared with 20 age and sex matched controls. There was substantial impairment in the latencies of all ABR waves as compared with control groups. They noted major delay in the peripheral (wave 1) and central transmission (wave 1-5) in the diabetic group. They also observed that the shift in wave 1 to 5 will be considerably increased if the stimulus repetition rates were increased.

A term called “central diabetic neuropathy” was put forward, which implies that the latency delays where considerably more in the components of ABR that occur late. This signifies that brainstem level involvement has occurred in patients with diabetes. This finding correlates well with the findings of Donald et al, Khardori et al and Virtaniemi et al^2,4,5

In our study, a statistically significant prolongation was observed in wave III latency at 70, 80 and 90 dBnHL in diabetic group compared to the control group. Similarly, the latency of wave V was significantly delayed in 70, 80 and 90dBnHL in diabetic group as compared to the controls with wave V being highly significant at 70 and 90 dB. There was no significant interaural latency difference.

Donald et al in their study conducted ABR tests on 20 IDDM patients and found that the latency of wave III, wave V, interwave latency I-III and I-V were significantly delayed.² For wave III the delay was by 0.30 ms (p<0.05- significant) and the delay in latency of wave V was by 0.45 ms (p<0.001- highly significant) on 70, 80, and 90 dB respectively. Likewise, the interpeak/interwave latency of wave I-III and the interpeak latency wave I-V was delayed by 0.24 ms (p<0.01) and 0.35 ms (p<0.05) respectively. The latency difference of wave I in study and control group in all the three intensities were not highly significant, suggesting that the 8^th nerve transmission till the level of the cochlear nucleus was not greatly altered in diabetics. ABR recordings based on the study by Durmus et al to measure the delays in neural conduction along the auditory pathway was done in 43 diabetes patients.⁶ The recordings from their study shown that the absolute latencies of waves I, III, and V were significantly delayed in the diabetes group compared to the control group (p<0.05).

Kurien et al did pure tone audiometry in 30 diabetic patients and 30 controls and found that diabetics had poorer hearing threshold than non-diabetics. All diabetic age groups showed significant high frequency hearing loss as compared to control population.⁷

In type 2 diabetic patients, latencies of waves I, II, III, IV and V and interpeak latencies IIII, I-V and III-V were significantly delayed. There was no statistically significant difference in latency delay between type 1 and type 2 DM. No relation was found with the duration of DM. Among individuals with long standing type 1 and type 2 DM, almost 50% develop neuropathic complications 88. The pathophysiology of neuronal degeneration in diabetes is unsure. Recently it has been proposed that in addition to compromised cell survival metabolism and neuronal plasticity, Insulin resistance in type-2 DM also increases oxidative stress and neuronal apoptosis89. As far as CNS involvement is concerned, a rise in ceramide generation and its preceding increase across the blood brain barrier encourages further insulin resistance and neurodegenerative changes in type-2DM patients. All diabetic patients should be screened for neuropathy of any kind annually as suggested by the American diabetes association.

At present the screening tool for diabetic neuropathy widely in practice is the nerve conduction study. Utilizing BERA/ABR in this scenario as a screening tool would be of great benefit.

In our study, we concluded that diabetes and BERA abnormalities are significantly associated which has also been substantiated by numerous preceding studies.

The global prevalence of diabetes keeps profoundly increasing day by day which directs us to investigate its complications and screen them from affecting the quality of life of the patient. Therefore, it is highly beneficial to include BERA/ABR in the investigative battery of tests in the long-standing diabetic population.

Limitations

The results can be precisely framed by adding more audiological and neurological tests, which can also be used to exclude other pathologies pertaining to specific sites, for example tests to include hair cell damage or neuronal damage in brain parenchyma.

Diabetes in the long run produces these complications, so it would be better if our research work targets the preventive aspect, i.e., in this case, to detect at the earliest for the society to be benefited as a whole.

CONCLUSION

Central acoustic neuropathy can be identified early with the help of BERA even if there is no clinically evident hearing loss. Thus, the results of BERA/ABR can assist the treating clinician for watchful control of the blood glucose level if it is not adequately controlled. BERA/ABR testing can be done on an annual basis which will help the physician to update their diabetic patient’s hearing status so that necessary guidance can be given to control it. Also helps to prevent the further progression of neuropathy is highly recommended. More similar studies are necessary and helpful not only for the standardization of BERA results in diabetics but also for detecting the association between BERA abnormalities and severity of diabetes with greater accuracy.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: The study was approved by the Institutional Ethics Committee

REFERENCES

1. 1. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Isselbacher KL. Harrison's Principles of Internal Medicine. 2005;6.
2. 2. Donald MW, Bird CE, Lawson JS, Letemendia FJJ, Monga TN, Urridge DHC et al. Delayed auditory brainstem responses in diabetes mellitus J Neurol Neurosurg Psychiatry. 1981;44(7):641-4.
3. 3. Fedele D, Martini A, Cardone C, Comacchio F, Bellavere F, Molinari G et al. Impaired auditory brainstem-evoked responses in insulin-dependent diabetic subjects. Diabetes. 1984;33;1085-9.
4. 4. Khardori R, Soler NG, Good DC, Devlesc Howard AB, Broughton D, Walbert J. Brainstem auditory and visual evoked potentials in type 1 (insulin-dependent) diabetic patients. Diabetologia. 1986;29(6):362-5.
5. 5. Virtanierni J, Laakso M, Nuutinen J, Karjalainens. Quoted by Booth JB. Scott Brown’s otolaryngology. 6^th ed, Butterworths, London. 1997;3:95.
6. 6. Durmus C, Yetiser S, Durmus O. Auditory brainstem evoked responses in insulin-dependent (ID) and non-insulin-dependent (NID) diabetic subjects with normal hearing. Int j audiol. 2004;43(1):29-33.
7. 7. Kurien M, Thomas K, Bhanu TS. Hearing threshold in patients with diabetes mellitus. J Laryngol Otol. 1989;103;164-8.
8. 8. King H, Aubert RE, Herman WH: Global burden of diabetes, 1995-2025: prevalence numerical estimates, and projections. Diabetes care. 1998;21(9):1414-31.
9. 9. Liu Z, Fu C, Wang W, Xu B. Prevalence of chronic complications of type 2 diabetes mellitus in outpatients - a cross-sectional hospital-based survey in urban China. Health Quality Life Outcomes. 2010;8:62.
10. 10. Maia CAS, Campos CAH. Diabetes Mellitus as etiological factor of hearing loss. Braz J Otorhinolaryngol. 2005;71(2):208-14.
11. 11. Di Leo MA, Di Nardo W, Cercone S, Ciervo A, Lo Monaco M, Greco AV et al. Cochlear dysfunction in IDDM patients with subclinical peripheral neuropathy. Diabetes Care. 1997;20(5):824-8.
12. 12. Marchiori LMM, Gibrin PCD. Diabetes mellitus: prevalência de alterações auditivas. Arq Bras Endocrinol Metab. 2003;47(1):82-6.
13. 13. Ferreira Jr. CA, Guimarães RES, Becker HMG, Silva CDL, Gonçalves TML, Crosara PFTB et al. Avaliação metabólica do paciente com labirintopatia. Arq Otorrinolaringol. 2000;4(1):28-32.
14. 14. Dall’Igna C, Batista LRP, Siqueira MK. Patogênese da disacusia neurossensorial em Diabetes Mellitus. Rev Bras Otorrinolaringol. 2000;66(2):155-8.
15. 15. Bittar RMB, Sanchez TG, Santoro PP, Medeiros IRT. O metabolism daglicose e o ouvido interno. Arq Fund Otorrinolaringológica. 1998;2(1):4-7.
16. 16. Wright A. Anatomy and Ultrastructure of human ear”, in Scott-Brown’s Otolaryngology, 6^th edition. 1997;1(1):1-49.
17. 17. Niparko JK, Richardson MA. Cummings Otolaryngology Head and Neck Surgery, edition 5, Mosby Elsiever, USA. 2010;3(7 and 8):1821-2956.
18. 18. Watkinson JC, Clarke RW. Scott Brown’s Otorhinolaryngology, Head and Neck Surgery, edition - 8, CRC PRESS, UK. 2018;2(46-53):56-73.
19. 19. Dhingra PL, Dhingra S. Diseases of Ear, Nose and Throat, 6^th Edition, ch. 1 and 2. Elsiever, India. 2014;1.
20. 20. Hayes SH, Ding D, Salvi RJ, Allman BL. Anatomy and physiology of the external, middle and inner ear. Handbook of Clinical Neurophysiology: New York: Elsevier. 2013;3-23.
21. 21. Rattay F, Danner SM. Peak I of the human auditory brainstem response results from the somatic regions of type I spiral ganglion cells: evidence from computer modeling. Hearing research. 2014;315:67-79.
22. 22. Akinpelu OV, Ibrahim F, Waissbluth S, Daniel SJ. Histopathologic changes in the cochlea associated with diabetes mellitus-a review. Otol Neurotol. 2014;35(5):764-74.
23. 23. Virtanierni J, Laakso M, Nuutinen J, Karjalainens. Quoted by Booth JB. Scott. Brown’s otolaryngology. 6^th ed. Butterworths, London. 1997;3:95.
24. 24. Scott Brown’s Otorhinolaryngology, Head and Neck Surgery, Chapters 226, edition 7^th CRC PRESS, UK. 2008;3.
25. 25. Brugge JF. Anatomy and physiology of auditory pathways and cortex. Handbook Clin Neurophysiol. 2013;10:25-59.
26. 26. Hackney CM. Anatomical features of the auditory pathway from cochlea to cortex. Brit med bull. 1987;43(4):780-801.
27. 27. Møller AR, Jannetta PJ. Compound action potentials recorded intracranially from the auditory nerve in man. Experimental neurol. 1981;74(3):862-74.
28. 28. Celesia GG. Disorders of Peripheral and Central Auditory Processing1: Disorders of Peripheral and Central Auditory Processing. Elsevier Health Sci. 2013.
29. 29. Friedman SA, Schulman RH, Weiss S. Hearing and Diabetic neuropathy. Arch Intern Med. 1975;135:573-6.
30. 30. Konrad-Martin D, Reavis KM, Austin D, Reed N, Gordon J, McDermott D, Dille MF. Hearing impairment in relation to severity of diabetes in a veteran cohort. Ear and hearing. 2015;36(4):381.
31. 31. Ren J, Ma F, Zhou Y, Xu A, Zhang J, Ma R et al. Hearing impairment in type 2 diabetics and patients with early diabetic nephropathy. J diabetes its complications. 2018;32(6):575-9.